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1
Neetz, Manuel. "Collective behavior of molecular motors." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-85935.
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Microtubule associated molecular motors are involved in a multitude of fundamental cellular processes such as intracellular transport and spindle positioning. During these movements multiple motor proteins often work together and are, therefore, able to exert high forces. Thus force generation and sensing are common mechanisms for controlling motor driven movement. These mechanisms play a pivotal role when motor proteins antagonize each other, e.g. to facilitate oscillations of the spindle or the nucleus.
Single motor proteins have been characterized in depth over the last two decades, our understanding of the collective behavior of molecular motors remains, however, poor. Since motor proteins often cooperate while they walk along microtubules, it is necessary to describe their collective reaction to a load quantitatively in order to understand the mechanism of many motor-driven processes.
I studied the antagonistic action of many molecular motors (of one kind) in a gliding geometry. For this purpose I crosslinked two microtubules in an antiparallel fashion, so that they formed \"doublets\". Then I observed the gliding motility of these antiparallel doublets and analyzed the gliding velocity with respect to the relative number of motors pulling or pushing against each other. I observed that the antiparallel doublets gliding on conventional kinesin-1 (from Drosophila melanogaster) as well as cytoplasmic dynein (from Saccharomyces cerevisae) exhibited two distinct modes of movement, slow and fast, which were well separated. Furthermore I found a bistability, meaning, that both kinds of movement, slow and fast, occurred at the same ratio of antagonizing motors. Antiparallel doublets gliding on the non-processive motor protein Ncd (the kinesin-14 from D. melanogaster) showed, however, no bistability. The collective dynamics of all three motor proteins were described with a quantitative theory based on single-motor properties.
Furthermore the response of multiple dynein motors towards an external, well-defined load was measured in a gliding geometry by magnetic tweezing. Examples of multi-motor force-velocity relationships are presented and discussed. I established, furthermore, a method for counting single surface immobilized motors to guide the evaluation of the tweezing experiments.
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Vilfan, Andrej. "Collective dynamics of molecular motors." [S.l. : s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=959980024.
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Jaster, Nicole. "Ratchet models of molecular motors." Phd thesis, Universität Potsdam, 2003. http://opus.kobv.de/ubp/volltexte/2005/90/.
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Transportvorgänge in und von Zellen sind von herausragender Bedeutung für das Überleben des Organismus. Muskeln müssen sich kontrahieren können, Chromosomen während der Mitose an entgegengesetzte Enden der Zelle bewegt und Organellen, das sind von Membranen umschlossene Kompartimente, entlang molekularer Schienen transportiert werden. <br />
Molekulare Motoren sind Proteine, deren Hauptaufgabe es ist, andere Moleküle zu bewegen. Dazu wandeln sie die bei der ATP-Hydrolyse freiwerdende chemische Energie in mechanische Arbeit um. Die Motoren des Zellskeletts gehören zu den drei Superfamilien Myosin, Kinesin und Dynein. Ihre Schienen sind Filamente des Zellskeletts, Actin und die Microtubuli. <br />
In dieser Arbeit werden stochastische Modelle untersucht, welche dazu dienen, die Fortbewegung dieser linearen molekularen Motoren zu beschreiben. Die Skala, auf der wir die Bewegung betrachten, reicht von einzelnen Schritten eines Motorproteins bis in den Bereich der gerichteten Bewegung entlang eines Filaments. Ein Einzelschritt überbrückt je nach Protein etwa 10 nm und wird in ungefähr 10 ms zurückgelegt. Unsere Modelle umfassen M Zustände oder Konformationen, die der Motor annehmen kann, während er sich entlang einer eindimensionalen Schiene bewegt. An K Orten dieser Schiene sind Übergänge zwischen den Zuständen möglich. Die Geschwindigkeit des Proteins lässt sich in Abhängigkeit von den vertikalen Übergangsraten zwischen den einzelnen Zuständen analytisch bestimmen. Wir berechnen diese Geschwindigkeit für Systeme mit bis zu vier Zuständen und Orten und können weiterhin eine Reihe von Regeln ableiten, die uns einschätzen helfen, wie sich ein beliebiges vorgegebenes System verhalten wird. <br />
Darüber hinaus betrachten wir entkoppelte Subsysteme, also einen oder mehrere Zustände, die keine Verbindung zum übrigen System haben. Mit einer bestimmten Wahrscheinlichkeit kann ein Motor einen Zyklus von Konformationen durchlaufen, mit einer anderen Wahrscheinlichkeit einen davon unabhängigen anderen. <br />
Aktive Elemente werden in realen Transportvorgängen durch Motorproteine nicht auf die Übergänge zwischen den Zuständen beschränkt sein. In verzerrten Netzwerken oder ausgehend von der diskreten Mastergleichung des Systems können auch horizontale Raten spezifiziert werden und müssen weiterhin nicht mehr die Bedingungen der detaillierten Balance erfüllen. Damit ergeben sich eindeutige, komplette Pfade durch das jeweilige Netzwerk und Regeln für die Abhängigkeit des Gesamtstroms von allen Raten des Systems. Außerdem betrachten wir die zeitliche Entwicklung für vorgegebene Anfangsverteilungen. <br />
Bei Enzymreaktionen gibt es die Idee des Hauptpfades, dem diese bevorzugt folgen. Wir bestimmen optimale Pfade und den maximalen Fluss durch vorgegebene Netzwerke. <br />
Um darüber hinaus die Geschwindigkeit des Motors in Abhängigkeit von seinem Treibstoff ATP angeben zu können, betrachten wir mögliche Reaktionskinetiken, die den Zusammenhang zwischen den unbalancierten Übergangsraten und der ATP-Konzentration bestimmen. Je nach Typ der Reaktionskinetik und Anzahl unbalancierter Raten ergeben sich qualitativ unterschiedliche Verläufe der Geschwindigkeitskurven in Abhängigkeit von der ATP-Konzentration. <br />
Die molekularen Wechselwirkungspotentiale, die der Motor entlang seiner Schiene erfährt, sind unbekannt.Wir vergleichen unterschiedliche einfache Potentiale und die Auswirkungen auf die Transportkoeffizienten, die sich durch die Lokalisation der vertikalen Übergänge im Netzwerkmodell im Vergleich zu anderen Ansätzen ergeben.<br>Transport processes in and of cells are of major importance for the survival of the organism. Muscles have to be able to contract, chromosomes have to be moved to opposing ends of the cell during mitosis, and organelles, which are compartments enclosed by membranes, have to be transported along molecular tracks.<br />
Molecular motors are proteins whose main task is moving other molecules.For that purpose they transform the chemical energy released in the hydrolysis of ATP into mechanical work. The motors of the cytoskeleton belong to the three super families myosin, kinesin and dynein. Their tracks are filaments of the cytoskeleton, namely actin and the microtubuli. <br />
Here, we examine stochastic models which are used for describing the movements of these linear molecular motors. The scale of the movements comprises the regime of single steps of a motor protein up to the directed walk along a filament. A single step bridges around 10 nm, depending on the protein, and takes about 10 ms, if there is enough ATP available. Our models comprise M states or conformations the motor can attain during its movement along a one-dimensional track. At K locations along the track transitions between the states are possible. The velocity of the protein depending on the transition rates between the single states can be determined analytically. We calculate this velocity for systems of up to four states and locations and are able to derive a number of rules which are helpful in estimating the behaviour of an arbitrary given system.<br />
Beyond that we have a look at decoupled subsystems, i.e., one or a couple of states which have no connection to the remaining system. With a certain probability a motor undergoes a cycle of conformational changes, with another probability an independent other cycle. <br />
Active elements in real transport processes by molecular motors will not be limited to the transitions between the states. In distorted networks or starting from the discrete Master equation of the system, it is possible to specify horizontal rates, too, which furthermore no longer have to fulfill the conditions of detailed balance. Doing so, we obtain unique, complete paths through the respective network and rules for the dependence of the total current on all the rates of the system. Besides, we view the time evolutions for given initial distributions. <br />
In enzymatic reactions there is the idea of a main pathway these reactions follow preferably. We determine optimal paths and the maximal flow for given networks. <br />
In order to specify the dependence of the motor's velocity on its fuel ATP, we have a look at possible reaction kinetics determining the connection between unbalanced transitions rates and ATP-concentration. Depending on the type of reaction kinetics and the number of unbalanced rates, we obtain qualitatively different curves connecting the velocity to the ATP-concentration. <br />
The molecular interaction potentials the motor experiences on its way along its track are unknown. We compare different simple potentials and the effects the localization of the vertical rates in the network model has on the transport coefficients in comparison to other models.
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Müller, Melanie J. I. "Bidirectional transport by molecular motors." Phd thesis, Universität Potsdam, 2008. http://opus.kobv.de/ubp/volltexte/2008/1871/.
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In biological cells, the long-range intracellular traffic is powered by molecular motors which transport various cargos along microtubule filaments. The microtubules possess an intrinsic direction, having a 'plus' and a 'minus' end. Some molecular motors such as cytoplasmic dynein walk to the minus end, while others such as conventional kinesin walk to the plus end. Cells typically have an isopolar microtubule network. This is most pronounced in neuronal axons or fungal hyphae. In these long and thin tubular protrusions, the microtubules are arranged parallel to the tube axis with the minus ends pointing to the cell body and the plus ends pointing to the tip.
In such a tubular compartment, transport by only one motor type leads to 'motor traffic jams'. Kinesin-driven cargos accumulate at the tip, while dynein-driven cargos accumulate near the cell body. We identify the relevant length scales and characterize the jamming behaviour in these tube geometries by using both Monte Carlo simulations and analytical calculations.
A possible solution to this jamming problem is to transport cargos with a team of plus and a team of minus motors simultaneously, so that they can travel bidirectionally, as observed in cells. The presumably simplest mechanism for such bidirectional transport is provided by a 'tug-of-war' between the two motor teams which is governed by mechanical motor interactions only. We develop a stochastic tug-of-war model and study it with numerical and analytical calculations. We find a surprisingly complex cooperative motility behaviour. We compare our results to the available experimental data, which we reproduce qualitatively and quantitatively.<br>In biologischen Zellen transportieren molekulare Motoren verschiedenste Frachtteilchen entlang von Mikrotubuli-Filamenten. Die Mikrotubuli-Filamente besitzen eine intrinsische Richtung: sie haben ein "Plus-" und ein "Minus-"Ende. Einige molekulare Motoren wie Dynein laufen zum Minus-Ende, während andere wie Kinesin zum Plus-Ende laufen. Zellen haben typischerweise ein isopolares Mikrotubuli-Netzwerk. Dies ist besonders ausgeprägt in neuronalen Axonen oder Pilz-Hyphen. In diesen langen röhrenförmigen Ausstülpungen liegen die Mikrotubuli parallel zur Achse mit dem Minus-Ende zum Zellkörper und dem Plus-Ende zur Zellspitze gerichtet.
In einer solchen Röhre führt Transport durch nur einen Motor-Typ zu "Motor-Staus". Kinesin-getriebene Frachten akkumulieren an der Spitze, während Dynein-getriebene Frachten am Zellkörper akkumulieren. Wir identifizieren die relevanten Längenskalen und charakterisieren das Stauverhalten in diesen Röhrengeometrien mit Hilfe von Monte-Carlo-Simulationen und analytischen Rechnungen.
Eine mögliche Lösung für das Stauproblem ist der Transport mit einem Team von Plus- und einem Team von Minus-Motoren gleichzeitig, so dass die Fracht sich in beide Richtungen bewegen kann. Dies wird in Zellen tatsächlich beobachtet. Der einfachste Mechanismus für solchen bidirektionalen Transport ist ein "Tauziehen" zwischen den beiden Motor-Teams, das nur mit mechanischer Interaktion funktioniert. Wir entwickeln ein stochastisches Tauzieh-Modell, das wir mit numerischen und analytischen Rechnungen untersuchen. Es ergibt sich ein erstaunlich komplexes Motilitätsverhalten. Wir vergleichen unsere Resultate mit den vorhandenen experimentellen Daten, die wir qualitativ und quantitativ reproduzieren.
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Qi, Fei. "Light-driven molecular rotary motors." HKBU Institutional Repository, 2017. https://repository.hkbu.edu.hk/etd_oa/434.
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In the past two decades, a number of artificial molecular motors have been constructed using organic molecules as components which can perform unidirectional motion. Among the best-known examples are the light-activated molecular rotary motors synthesized and analyzed in B. L. Feringa's lab. Yet there is limited understanding of the photoisomerization and thermal isomerization processes that control the speed and energy conversion efficiency of these molecular devices. The present thesis work aims at: 1) developing a computational methodology to provide the atomic and electronic details that allow for quantitative descriptions of light-activated molecular motion, 2) improving the understanding of the physical principles governing photo- and thermal-isomerization processes in specific molecular systems, and 3) proposing a new strategy of molecule design to assist experimental investigations. A key component in our methodology is the calculation of the potential energy surface (PES) spanned by collective atomic coordinates using ab initio quantum mechanical methods. This is done both for the electronic ground state, which is relatively straightforward, and for the photo-excited state, which is more involved. Once the PES is known, classical statistical mechanical methods can be used to analyze the dynamics of the slow variables from which information about the rotational motion can be extracted. Calculation of the PES is computationally expensive if one were to sample the very high dimensional space of the atomic coordinates. A new method, based on the torque experienced by individual atoms, is developed to capture key aspects of the intramolecular relaxation in terms of angular variables associated with the rotational degrees of freedom. The effectiveness of the approach is tested on specific light-driven molecular rotary motors that were successfully synthesized and analyzed in previous experiments. Finally, based on the experience accumulated in this study, a new molecular rotary motor driven by visible light is proposed to reach MHz rotational frequency.
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Keller, Peter. "Mathematical modeling of molecular motors." Universität Potsdam, 2013. http://opus.kobv.de/ubp/volltexte/2013/6304/.
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Amongst the many complex processes taking place in living cells, transport of cargoes across the cytosceleton is fundamental to cell viability and activity. To move cargoes between the different cell parts, cells employ Molecular Motors. The motors operate by transporting cargoes along the so-called cellular micro-tubules, namely rope-like structures that connect, for instance,
the cell-nucleus and outer membrane. We introduce a new Markov Chain, the killed Quasi-Random-Walk, for such transport molecules and derive properties like the maximal run length and time. Furthermore we introduce permuted balance, which is a more flexible extension of the ordinary reversibility and introduce the notion of Time Duality, which compares certain passage times pathwise. We give a number of sufficient conditions for Time Duality based on the geometry of the transition graph. Both notions are closely related to properties of the killed Quasi-Random-Walk.
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Pérez, Carrasco Rubén. "Mechano–chemical study of rotatory molecular motors." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/108039.
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Cells are the minimum unit of life. They are born, they eat, the may grow, they may move, and, eventually, they die. By contrast, from a physicist point of view, cells are systems out of equilibrium continuously transducing between matter, energy and information. This transduction is what grants the cell their active properties. In order to perform such tasks, cells have a set of macromolecules, a machinery, which are called, Molecular Motors or Molecular Machines. The operation of molecular motors is multiple. For instance, kinesins are molecular motors able to transport cargoes along the cell, or the Bacterial Flagellar Motor works as a nanometric ionic turbine transmitting its rotation to bacterial flagella propelling the cell.
The energy input of such nanometric devices have two primary sources. On one hand the hydrolysis of nucleotide derivatives, such as ATP. On the other hand, molecular motors can also be found in biological membranes obtaining energy from the natural flux of ions crossing the membrane due to mechano-chemical energetic differences at each side.
The recycling of ATP molecules takes place in another molecular machine, the F0F1 ATP synthase. F0F1 is made up of two subunits that can be separated themselves in two different molecular machines. This way, the F1 motor can couple a rotatory motor with the synthesis/hydrolysis of ATP.
Understanding the working of molecular motors is not straightforward. The transduction processes result from a complex set of interactions of all the molecules conforming the motor plus all the interactions with the surrounding molecules. Thus, different approaches with different levels of abstraction are necessary. In the current thesis, molecular motors are studied through the identification of the energetic transduction cycles out of the trajectory of the motor. Trajectories allow to identify the different mechanical and chemical processes driving the motor and allow to propose a spatio-temporal potential for the motor that give information of the energetic performance of the motor such as power and efficiency.
This analysis is performed on the F1 motor (in its hydrolysis regime). Such analysis allowed to identify the origin of two well differentiated mechanical and chemical processes that were quantified by means of the reaction kinetics theory and the overdamped dynamics associated with the nanometric biological scale. From this analysis resulted a prediction for the average velocity of the motor with the experimental control parameters. The resulting velocity matches experimental measures of the average velocity without fitting any parameter since all the parameters needed can be extracted from alternative experimental assays.
The appealing results of the average velocity lead to a proposal of motor potential for the F1 motor consisting on two linear piece-wise potentials flashing between them. Each potential presenting the experimental characteristics observed when the catalytic site of the motor is empty or occupied. The potential also hold the substepping mechanism observed experimentally. Thus, the resulting potential can be tested, together with the overdamped dynamics of the potential and the thermal fluctuations characteristic of the biological cellular scale. This results in a Langevin equation leading the dynamics of the motor. Again, the stochastic dynamics proposed are able to reproduce the velocity of the motor returning a better approximation than the deterministic approach. As happened in the previous case, there is no fitting in the parameters to test the validity of the velocity expression. Actually, the model is able to predict the measured substep angle from optimisation arguments. The mismatch between the deterministic and the stochastic results was identified as a result of a loss of ATP hydrolysis events due to thermal fluctuations that has been also properly quantified through the Fokker-Planck formalism of the corresponding Langevin equation.
The motor potential proposed was also used to study experimental assays of the F1 motor working against conservative forces. The effect of a conservative torque in the working of the motor contains contributions both mechanical and chemical. Altogether, this contributions were successfully addressed presenting again an analytical and stochastic prediction for the velocity of the motor that matches the experimental observations without the need of any parameter fitting. This analysis also entailed a study of the energetic performance of the motor which is unavailable experimentally. The results show a complete divergence between the stochastic and deterministic predictions. The divergence is specially dramatical near the stall force of the motor where the determenistic analysis predicts an efficiency maximum and the stochastic analysis returns a null efficiency. This points out that the stochastic effects are very relevant to the energetic performance of the motor and can not be missed in a proper energetic study of a molecular machine.
Besides the study of the F1 motor, also a rotatory device working with an ionic flux was analised. The aim of the analysis was the devise of a minimal mechanistic turbine and the study of its main working features. Such a machine is composed by a mobile piston with periodic boundary conditions at both ends of a nanometric channel separating two particle reservoirs. Hence, the turbine is able to transduce energy between the flux of ions and an external force hindering the natural motion of the piston. Again, thermal fluctuations provide a stochastic dynamic that must be studied through a Langevin equation that can be tackled analytically. This study revealed that the velocity and the flux are not coupled. Specially, two different stall forces appear for the motor. One for the velocity and one for the flux. This results in an intermediate zone where there is a continuous leakage of ions that does not allow any energetic output. This effect is originated from thermal fluctuations. Thus, when the energetic performance is evaluated, a similar behaviour than the one obtained for the F1 motor is recuperated. This minimal model was extended with more complex turbines that take into account more thoroughly the biophysics of molecular machines. All of them result in the same energetic landscape where a minimum of efficiency is obtained near the stall of the motor.
Additionally, a new formalism has been developed to simplify the resulting Langevin equations (Fokker-planck white noise limit) and a new algorithm has been devised able to integrate Langevin equations with non-continuous multiplicative noise<br>Los Motores Moleculares son macromoléculas biológicas que se encargan de hacer las transducciones energéticas necesarias dentro de las células. Este trabajo estudia la transformación de energía de motores moleculares rotatorios reales principalmente la F1-ATPasa, el Motor Flagelar de las Bacterias y el F0.
Para estudiar la dinámica del motor se han utilizado ecuaciones de Langevin sobreamortiguadas que recogen la importancia de las fluctuaciones térmicas, así como las fuerzas externas aplicadas al motor (conservativas y disipativas) y el potencial interno del motor que contiene la información físico-química de su comportamiento.
Este estudio se ha aplicado a la F1-ATPasa, que se puede estudiar tanto analíticamente, obviando las fluctuaciones térmicas como desde su naturaleza estocástica mediante potenciales intermitentes. En ambos casos, el modelo es capaz de describir la dinámica del motor y su dependencia con los diferentes parámetros controlables experimentalmente: Concentración de ATP, fuerza disipativa y fuerza conservativa.
En el mismo sentido se ha diseñado una turbina nanoscópica que recoge los principios básicos de la interacción mecánica entre un flujo de iones y la rotación del motor. En ambos casos, tanto en la turbina como en el F1 se observa que el ruido térmico no afecta mucho a la velocidad del motor y en cambio produce cambios enormes en parámetros energéticos como la potencia o la eficiencia. Concretamente, el escenario clásico en que un máximo de eficiencia se obtiene para la fuerza de calado desaparece obteniendo nuevos regímenes óptimos de trabajo.
Adicionalmente, se ha desarrollado un formalismo para simplificar las ecuaciones de Langevin obtenidas (límite de ruido blanco) y se ha diseñado un nuevo algoritmo para integrar ecuaciones de Langevin en las cuales el ruido multiplicativo es discontinuo en el espacio.
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Li, Quan. "Integrated motions of light driven molecular motors at macroscopic scale." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAF001/document.
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Dans la nature, des moteurs moléculaires tells que l'ATP synthase ou la kinésine peuvent consommer de l'énergie pour générer du mouvement et ainsi assurer des fonctions essentielles comme le transport ou la synthèse de molécules. La préparation de moteurs artificiels capables de fournir un travail à différentes échelles est un défi important pour les chimistes. Dans ce travail, nous avons conçu et synthétisé de manière stéréosélective un moteur moléculaire unidirectionnel et hautement fonctionnalisé à l'échelle du gramme. La fonctionnalisation orthogonale du moteur permet de l'intégrer dans des matériaux polymères. Grâce à une réaction de "click" réalisée sous différentes conditions de dilution, nous avons pu obtenir soit une macromolécule bicyclique en forme de 8 soit un gel de polymers dont les moteurs constituent les points de réticulation. Sous irradiation UV, les moteurs tournent ce qui enroule les chaines de polymers. Pour le bicycle, la taille caractéristique de la macromolécule diminue tandis que la morphologie évolue vers une pelote étirée. Dans le cas du gel, suite à la rotation des moteurs, l'enroulement des chaines conduit à une contraction du gel de l'ordre de 80% en volume. C'est le premier exemple d'intégration de mouvements moléculaires hors équilibre résultant en une réponse observable à l'échelle macroscopique. Ce travail ouvre des perspectives intéressantes dans le domaine des nanotechnologies ainsi que dans celui de l'énergie<br>Natural molecular motors such as ATP synthase, myosin, kinesin and dynein can convert conformationalchanges, due to chemical energy input, into directed motion for catalysis and transport. Preparing artificial molecular motors and making them work at different scales (from nano to macroscopic scale) have been long-term challenges. Herein we designed and synthesized a light driven rotary molecular motor in highly enantiopure form and in gram scale. This motor is featured by two orthogonal functionalities on its upper and lower part, allowing its further integration into polymeric materials. By performing click reaction under different concentration conditions, either an eight shaped motor-polymer conjugate or a gel containing motors as reticulation units could be obtained. Upon UV irradiation, the polymer chains could be entangled due to the rotation of this motor. For eight shaped polymer, the dimension was changed towards smaller dimension, and the morphology was changed from cycle to collapsed coils (spherical or more elongated). For the gel, due to the twisting of polymer chains induced by the rotation of the motor, it could be contracted significantly (80 %) compared with its original volume. The integration of machines which display motions out of equilibrium at nanoscale to movement in the macroscopic world which is extensively used in natural systems will open very interesting prospects in nanotechnology for further developments
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Simoes, Fabio Andre Amaral Lopes. "Cytoskeleton and molecular motors in the causation of motor neuron diseases." Thesis, University of Brighton, 2018. https://research.brighton.ac.uk/en/studentTheses/2629bd8d-bbba-4360-9ba2-d77733e431ad.
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Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy with lower extremity predominance (SMA-LED) are motor neuron diseases defined by the loss of motor neurons. RNA metabolism and molecular transport have both become increasingly implicated in the pathogenesis of motor neuron diseases. As such, this thesis explores the role of TAR-DNA binding protein 43 (TDP-43) in the regulation of peripherin expression in ALS, and the molecular consequences of mutations in DYNC1H1, a component of the cytoplasmic dynein motor complex, in SMA-LED. TDP-43 is a DNA/RNA binding protein implicated in ALS pathogenesis. Recent evidence suggests that TDP-43 regulates peripherin, an ALS associated intermediate filament protein. Here, analysis of peripherin in the lumbar spinal cord of TDP-43<sup>+/F210I</sup> mice revealed a significant increase in the levels of Per-45, a shift towards an increase in Per-58 in the Triton X-100 soluble fraction that did not reach statistical significance, and an increase in an isoform of 50 kDa in the insoluble fraction. These changes in the expression of peripherin in TDP-43<sup>+/F210I</sup> mice may indicate a regulatory role for TDP-43 in peripherin expression, which could contribute to ALS pathology. Furthermore, there is evidence that defects in neurodevelopment are present in SMA-LED. Analysis of paxillin, a key focal adhesion protein in mouse embryonic fibroblasts from the Legs at odd angles (Loa) model of SMA-LED was performed, which indicated a reduction in its expression which may underpin the previously reported migration phenotypes in these cells. This data provides further evidence that SMA-LED may be a neurodevelopmental disorder. Furthermore, analysis revealed that the Golgi apparatus in DYNC1H1<sup>+/D338N</sup> patient fibroblasts was significantly condensed, while in BICD2<sup>+/I189F</sup> fibroblasts there was a decrease in localisation of dynein to the Golgi. The lack of dynein at the Golgi in BICD2<sup>+/I189F</sup> fibroblasts indicates that BICD2 may be necessary for the recruitment of the molecular motor to the organelle. These Golgi phenotypes may also contribute to impaired migration in disease. Importantly, analysis of DYNC1H1<sup>+/D338N</sup> patient fibroblasts and mouse embryonic fibroblasts (MEFs) from the Loa mouse strain showed a significant decrease in α-tubulin acetylation, a phenotype previously seen in another DYNC1H1 substitution. In conclusion, these data support previous data which suggested that peripherin expression is altered in the context of TDP-43 mutations, potentially contributing to ALS pathology. Additionally, Golgi phenotypes were found in both DYNC1H1<sup>+/D338N</sup> and BICD2<sup>+/I189F</sup> fibroblasts with potential consequences for cellular migration. Finally, decreased microtubule acetylation may be a common factor in SMA-LED linked with DYNC1H1 mutations. The conserved nature of this phenotype could indicate a potential target for therapeutics.
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Ökten, Zeynep. "Single molecule mechanics and the myosin family of molecular motors." [S.l.] : [s.n.], 2006. http://www.diss.fu-berlin.de/2006/6/index.html.
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Hugel, Thorsten. "Towards Synthetic Molecular Motors Interfaced by AFM." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-8157.
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Ramsdell, Talia Lynn. "Molecular Motors of ESX-Type Secretion Systems." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10212.
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Tuberculosis is an enormous global health problem. Despite decades of research, the mechanism(s) by which Mycobacterium tuberculosis (Mtb) mediates virulence remains incompletely understood. The ESX-1 secretion system is critical for Mtb to survive and cause disease in vivo, but its primary function and mechanism of action are unclear. The many inherent challenges of working with this slow-growing pathogen often limit the experimental approaches that can be used to address these questions. Thus, we have developed a model system in the nonpathogenic bacterium Bacillus subtilis to study ESX-type secretion systems. Here, we demonstrate that the B. subtilis yuk operon encodes an ESX-type secretion system responsible for the secretion of YukE. Additionally, we demonstrate that the yuk system is active in B. subtilis during conditions of nutrient deprivation and is required for normal biofilm formation. Interestingly, this is similar to our findings that the Mtb ESX-1 system plays dual roles in protein secretion and modulating cell wall integrity. One defining feature of all ESX loci is the presence of an FtsK/SpoIIIE family ATPase. Interestingly, these ATPases have a domain structure unique to ESX-associated ATPases, where each protein contains multiple (2-3) enzymatic domains. We used our B. subtilis system to dissect the mechanism of action of this unique class of motor proteins. We find that the yuk-encoded ATPase YukBA dimerizes to form a hexamer of enzymatic subunits that are differentially required for secretion. Strikingly, we find a unique requirement for rotational symmetry in the nucleotide binding activity of the subunits. Finally, we compared the energy requirements of the Mtb ESX-1 system and the B. subtilis yuk system. We find that these systems have some overlapping ATPase requirements for protein secretion and cell wall integrity/biofilm formation, suggesting that there is a conservation of function among ESX-type systems. We also find that some ATPase domains are differentially required for function between these two systems, which we postulate is due to the split protein architecture of the ESX-1-encoded ATPases. Together, these findings highlight the power of using a B. subtilis model system to understand the function and mechanism of action of ESX-type secretion systems.
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Su, Xiaolei. "Regulation of Microtubule Dynamics by Molecular Motors." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10145.
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Kinesin superfamily motors have a well-characterized ability to move along microtubules and transport cargo. However, some members of the kinesin superfamily can also remodel microtubule networks by controlling tubulin polymerization dynamics and by organizing microtubule structures. The kinesin-8 family of motors play a central role in cellular microtubule length control and in the regulation of spindle size. These motors move in a highly processive manner along the microtubule lattice towards plus ends. Once at the microtubule plus end, these motors have complex effects on polymerization dynamics: kinesin-8s can either destabilize or stabilize microtubules, depending upon the context. My thesis work identified a tethering mechanism that facilitates the processivity and plus end-binding activity of Kip3 (kinesin-8 in budding yeast), which is essential for the destabilizing activity of kinesin-8 in cells. A concentration-dependent model was proposed to explain the divergent effects of Kip3 on microtubule dynamics. Moreover, a novel activity of Kip3 in organizing microtubules was discovered: Kip3 can slide anti-parallel microtubules apart. The sliding activity of Kip3 counteracts the depolymerizing activity of Kip3 in controlling spindle length and stability. A lack of sliding activity causes fragile spindles during the process of chromosome segregation in anaphase. The tail domain of Kip3, which binds both microtubules and tubulin dimers, plays a critical role in all these activities. Together, my work defined multiple mechanisms by which Kip3 remodels the microtubule cytoskeleton. The physiological importance of these regulatory mechanisms will be discussed.
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Klumpp, Stefan. "Movements of molecular motors : diffusion and directed walks." Phd thesis, [S.l. : s.n.], 2003. http://pub.ub.uni-potsdam.de/2003/0020/klumpp.pdf.
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Kuwada, Nathan James 1983. "Simulation studies of Brownian motors." Thesis, University of Oregon, 2010. http://hdl.handle.net/1794/11298.
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xii, 122 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number.<br>Biological molecular motors achieve directed motion and perform work in an environment dominated by thermal noise and in most cases incorporate thermally driven motion into the motor process. Inspired by bio-molecular motors, many other motor systems that incorporate thermal motion have been developed and studied. These motors are broadly referred to as Brownian motors. This dissertation presents simulation studies of two particular Brownian motors, the feedback-controlled flashing ratchet and an artificial molecular motor concept, the results of which not only drive experimental considerations but also illuminate physical behaviors that may be applicable to other Brownian motors.
A flashing ratchet rectifies the motion of diffusive particles using a time dependent, asymmetric potential energy landscape, and the transport speed of the ratchet can be increased if information about the particle distribution is incorporated as feedback in the time dependency of the landscape. Using a Langevin Dynamics simulation, we compare two implementations of feedback control, a discrete algorithm and a continuous algorithm, and find that the discrete algorithm is less sensitive to fluctuations in the particle distribution. We also model an experimental system with time delay and find that the continuous algorithm can be improved by adjusting the feedback criteria to react to the expected state of the system after the delay time rather than the real-time state of the system.
Motivated by the desire to understand bio-molecular linear stepping motors, we present a bottom-up approach of designing an artificial molecular motor. We develop a coarse-grained Molecular Dynamics model that is used to understand physical contributions to the diffusive stepping time of the motor and discover that partially reducing the diffusional space from 3D to 1D can dramatically increase motor speed. We also develop a stochastic model based on the classical Master equation for the system and explore the sensitivity of the motor to currently undetermined experimental parameters. We find that a reduced diffusional stepping time is critical to maintain motor attachment for many successive steps and explore an experimental design effect that leads to motor misstepping.<br>Committee in charge: Stephen Kevan, Chairperson, Physics;
Heiner Linke, Member, Physics;
John Toner, Member, Physics;
Raghuveer Parthasarathy, Member, Physics;
Marina Guenza, Outside Member, Chemistry
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Craig, Erin Michelle. "Models for Brownian and biomolecular motors /." Connect to title online (Scholars' Bank) Connect to title online (ProQuest), 2008. http://hdl.handle.net/1794/8565.
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Thesis (Ph. D.)--University of Oregon, 2008.<br>Typescript. Includes vita and abstract. Includes bibliographical references (leaves 164-171). Also available online in Scholars' Bank; and in ProQuest, free to University of Oregon users.
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Oriola, Santandreu David. "Self-organization and cooperativity of cytoskeletal molecular motors." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/396083.
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The present work deals with different aspects concerning the collective action of cytoskeletal molecular motors. The thesis is organized in two parts: the first part corresponds to the study of the cooperative action of molecular motors in intracellular transport, whereas the second part corresponds to the study of oscillatory dynamical instabilities driven by molecular motors.
In the first part of the thesis, we carry out complete theoretical and experimental studies on the single-headed kinesin KIF1A, which constitutes a remarkable example of Brownian motor and a model motor to study intracellular transport.
We provide a thorough numerical study of the collective action of single-headed KIF1A motors based on Brownian dynamics. We predict a dramatic improvement of the collective performance of these motors for tasks associated to the transport of membrane-bound cargoes. From a biological point of view, our results reinforce the hypothesis that the specificity of KIF1A to axonal vesicular trafficking is due to its unique adaptation to cooperative force generation. From a fundamental physics point of view, we show that Brownian motors based on two-state ratchets with independent switching and under unequal loading are remarkably adapted to cooperative force generation. We further test our predictions using a lattice model to study the dynamics of two interacting KIF1A motors. We show analytically the presence of cooperativity in the system and we consider a first extension of the problem to an arbitrary number of motors.
Finally, we test our theoretical predictions experimentally, by using biomimetic tube pulling assays with single-headed KIF1A motors. We show that, despite the extreme inefficieny of the individual motors, they are able to cooperate collectively to extract membrane tubes, thus validating our theoretical predicitions. Additionally, we find the surprising formation of helical tubes around microtubules. This entails an impressive capability of single-headed KIF1A motors to exert significant off-axis by virtue of a diffusive state. Accordingly, this state affords two complementary strategies to overcome obstructions: brute force and manoeuvreing capability. In a series configuration (in line) it enables the generation of large forces by accumulation of motors, whereas in a parallel configuration (side by side) it enables lateral displacement of the cargo.
In the second part of the thesis, we study the generation of dynamical instabilities driven by molecular motors. In particular, the spontaneous oscillations in a minimal in vitro actomyosin system and the self-organized flagellar beating driven by axonemal dynein.
In the first case, we study theoretically an actomyosin system coupled to an elastic element, generating spontaneous oscillations in the presence of ATP via a Hopf bifurcation. This problem mimics the mechanism responsible of the asynchronous wing thrust observed in some insect species. We show that the theoretical model, based on an integro-differential system of equations, can be reduced to a simple three-dimensional ODE system. We find that both the complete and reduced systems exhibit subharmonic oscillations in some regimes. Remarkably, subharmonic peaks were reported experimentally in the signal power spectrum of a minimal in vitro actomyosin system. Hence, we provide an explanation for this phenomenon.
In the second case, we study the nonlinear dynamics of axonemal beating driven by molecular motors. The explicit nonlinear equations for the flagellar shape and dynein kinetics are derived and solved numerically. Our analysis reveals the spatiotemporal dynamics of dynein kinetics and flagellum shape for different regimes of motor activity, medium viscosity and flagellum elasticity. We find that far from the bifurcation, linearized solutions fail to describe the flagellar shape and nonlinear effects arise in the system solely due to motor activity. Finally, we further characterize flagellar dynamics using principal component analysis and studying bending initiation.<br>Els enormes progressos de les nanotecnologies durant les últimes dècades han permès un estudi quantitatiu dels fenòmens biològics fins arribar a l'escala d'una sola molècula. La possibilitat de visualitzar, manipular i mesurar fenòmens biològics a escala molecular obre un nou món per a la física, que pot aplicar els seus mètodes de modelització per a explicar i predir fenòmens abans inabastables des d'un punt de vista tecnològic. És en aquest marc on disciplines com ara la física estadística de no equilibri, la física no lineal o la ciència de materials tous conflueixen i juguen un paper clau. La complexitat dels sistemes biològics rau comunament en fenòmens col.lectius en situacions allunyades del equilibri, autoregulats mitjançant xarxes bioquímiques complexes les quals requereixen d'un alt grau d'autoorganització, la qual cosa implica tant fluxes de matèria i energia com d'informació. Tot i així, els nivells d'autoorganització i autoregulació involucrats en funcions cel.lulars tals com la motilitat i el tràfic intern, estan encara molt lluny d'una comprensió quantitativa satisfactòria des d'un punt de vista físic. Tals processos requereixen no només d'una visió qualitativa i descriptiva sinó també d'una perspectiva físico-matemàtica per a la seva completa comprensió.
El present treball versa sobre l'estudi de l'acció col.lectiva de motors moleculars del citoesquelet, amb la finalitat de contribuir en la comprensió de la generació de força i moviment dins la cèl.lula. La tesi està estructurada en dues parts: la primera part correspon a l'estudi del transport intracel•lular degut a l'acció cooperativa de motors, en particular, l'estudi es centra en la kinesina monomèrica KIF1A, la qual constitueix un exemple notable de motor Brownià en el context biològic. En primer lloc es duu a terme un estudi teòric exhaustiu sobre l'acció col.lectiva d'aquests motors i posteriorment es validen experimentalment els resultats predits anteriorment mitjançant experiments d'extracció de tubs de membrana. En la segona part, s'estudia la generació d'inestabilitats dinàmiques degudes a l'acció cooperativa de motors moleculars. En particular, es tracten el casos d'oscil.lacions espontànees generades per un sistema in vitro d'actina i miosina, i el batec autoorganitzat de fagels degut a l'acció de dineïnes axonèmiques.
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Berger, Florian. "Different modes of cooperative transport by molecular motors." Phd thesis, Universität Potsdam, 2012. http://opus.kobv.de/ubp/volltexte/2012/6031/.
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Cargo transport by molecular motors is ubiquitous in all eukaryotic cells and is typically driven cooperatively by several molecular motors, which may belong to one or several motor species like kinesin, dynein or myosin. These motor proteins transport cargos such as RNAs, protein complexes or organelles along filaments, from which they unbind after a finite run length. Understanding how these motors interact and how their movements are coordinated and regulated is a central and challenging problem in studies of intracellular transport. In this thesis, we describe a general theoretical framework for the analysis of such transport processes, which enables us to explain the behavior of intracellular cargos based on the transport properties of individual motors and their interactions. Motivated by recent in vitro experiments, we address two different modes of transport: unidirectional transport by two identical motors and cooperative transport by actively walking and passively diffusing motors.
The case of cargo transport by two identical motors involves an elastic coupling between the motors that can reduce the motors’ velocity and/or the binding time to the filament. We show that this elastic coupling leads, in general, to four distinct transport regimes. In addition to a weak coupling regime, kinesin and dynein motors are found to exhibit a strong coupling and an enhanced unbinding regime, whereas myosin motors are predicted to attain a reduced velocity regime. All of these regimes, which we derive both by analytical calculations and by general time scale arguments, can be explored experimentally by varying the elastic coupling strength. In addition, using the time scale arguments, we explain why previous studies came to different conclusions about the effect and relevance of motor-motor interference. In this way, our theory provides a general and unifying framework for understanding the dynamical behavior of two elastically coupled molecular motors.
The second mode of transport studied in this thesis is cargo transport by actively pulling and passively diffusing motors. Although these passive motors do not participate in active transport, they strongly enhance the overall cargo run length. When an active motor unbinds, the cargo is still tethered to the filament by the passive motors, giving the unbound motor the chance to rebind and continue its active walk. We develop a stochastic description for such cooperative behavior and explicitly derive the enhanced run length for a cargo transported by one actively pulling and one passively diffusing motor. We generalize our description to the case of several pulling and diffusing motors and find an exponential increase of the run length with the number of involved motors.<br>Lastentransport mittels Motorproteinen ist ein grundlegender Mechanismus aller eukaryotischen Zellen und wird üblicherweise von mehreren Motoren kooperativ durchgeführt, die zu einer oder zu verschiedenen Motorarten wie Kinesin, Dynein oder Myosin gehören. Diese Motoren befördern Lasten wie zum Beispiel RNAs, Proteinkomplexe oder Organellen entlang Filamenten, von denen sie nach einer endlichen zurückgelegten Strecke abbinden. Es ist ein zentrales und herausforderndes Problem zu verstehen, wie diese Motoren wechselwirken und wie ihre Bewegungen koordiniert und reguliert werden. In der vorliegenden Arbeit wird eine allgemeine theoretische Herangehensweise zur Untersuchung solcher Transportprozesse beschrieben, die es uns ermöglicht, das Verhalten von intrazellularem Transport, ausgehend von den Transporteigenschaften einzelner Motoren und ihren Wechselwirkungen, zu verstehen. Wir befassen uns mit zwei Arten kooperativen Transports, die auch kürzlich in verschiedenen in vitro-Experimenten untersucht wurden: (i) gleichgerichteter Transport mit zwei identischen Motorproteinen und (ii) kooperativer Transport mit aktiv schreitenden und passiv diffundierenden Motoren.
Beim Lastentransport mit zwei identischen Motoren sind die Motoren elastisch gekoppelt, was eine Verminderung ihrer Geschwindigkeit und/oder ihrer Bindezeit am Filament hervorrufen kann. Wir zeigen, dass solch eine elastische Kopplung im Allgemeinen zu vier verschiedenen Transportcharakteristiken führt. Zusätzlich zu einer schwachen Kopplung, können bei Kinesinen und Dyneinen eine starke Kopplung und ein verstärktes Abbinden auftreten, wohingegen bei Myosin Motoren eine verminderte Geschwindigkeit vorhergesagt wird. All diese Transportcharakteristiken, die wir mit Hilfe analytischer Rechnungen und Zeitskalenargumenten herleiten, können durch Änderung der elastischen Kopplung experimentell untersucht werden. Zusätzlich erklären wir anhand der Zeitskalenargumente, warum frühere Untersuchungen zu unterschiedlichen Erkenntnissen über die Auswirkung und die Wichtigkeit der gegenseitigen Beeinflussung der Motoren gelangt sind. Auf diese Art und Weise liefert unsere Theorie eine allgemeine und vereinheitlichende Beschreibung des dynamischen Verhaltens von zwei elastisch gekoppelten Motorproteinen.
Die zweite Art von Transport, die in dieser Arbeit untersucht wird ist der Lastentransport durch aktiv ziehende und passiv diffundierende Motoren. Obwohl die passiven Motoren nicht zum aktiven Transport beitragen, verlängern sie stark die zurückgelegte Strecke auf dem Filament. Denn wenn ein aktiver Motor abbindet, wird das Lastteilchen immer noch am Filament durch den passiven Motor festgehalten, was dem abgebundenen Motor die Möglichkeit gibt, wieder an das Filament anzubinden und den aktiven Transport fortzusetzen. Für dieses kooperative Verhalten entwickeln wir eine stochastische Beschreibung und leiten explizit die verlängerte Transportstrecke für einen aktiv ziehenden und einen passiv diffundierenden Motor her. Wir verallgemeinern unsere Beschreibung für den Fall von mehreren ziehenden und diffundierenden Motoren und finden ein exponentielles Anwachsen der zurückgelegten Strecke in Abhängigkeit von der Anzahl der beteiligten Motoren.
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Khataee, Gavgani Hamidreza. "Theoretical Investigation of Intracellular Transport by Molecular Motors." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/368174.
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Molecular motors are protein nanomachines that organize the internal order of all eukaryotic cells by shuttling intracellular cargos. Kinesins, dyneins, and myosins are three identified superfamilies of molecular motors which often function together within the cells. All of these motors power cellular motility using energy derived from adenosine triphosphate (ATP) hydrolysis. Molecular biology has revealed that the functional impairments of molecular motors would contribute to various human diseases, such as Alzheimer and cancer. Engineering developments have also emerged regarding the utilization of molecular motors in nanorobotics with a variety of missions, such as molecular communications. Despite this progress, the properties of intracellular cargo transport are not well understood. Motivated by the recent experimental findings, this thesis proposes computational and mathematical frameworks to investigate two different modes of intracellular cargo transport driven by (i) a single motor and by (ii)
an assembly of two coupled identical motors. We focus on the cargo transport by kinesins because kinesin stepping kinetic scheme has been developed previously, and recent experiments have further measured input parameters for our theory. Nevertheless, our models are rather general and can be applied to other types of cytoskeletal molecular motors.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Information and Communication Technology<br>Science, Environment, Engineering and Technology<br>Full Text
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Grover, Rahul. "Transport by kinesin motors diffusing on a lipid bilayer." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-200330.
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Intracellular transport of membrane-bound vesicles and organelles is a process fundamental for many cellular functions including cell morphogenesis and signaling. The transport is mediated by ensembles of motor proteins, such as kinesins, walking on microtubule tracks. When transporting membrane-bound cargo inside a cell, the motors are linked to diffusive lipid bilayers either directly or via adaptor molecules. The fluidity of the lipid bilayers induces loose inter-motor coupling which is likely to impact the collective motor dynamics and may induce cooperativity. Here, we investigate the influence of loose coupling of kinesin motors on its transport characteristics.
In the first part of this thesis, we used truncated kinesin-1 motors with a streptavidin-binding-peptide (SBP) tag and performed gliding motility assays on streptavidin-loaded biotinylated supported lipid bilayers (SLBs), so called ‘membrane-anchored’ gliding motility assays. We show that the membrane-anchored motors act cooperatively; the microtubule gliding velocity increases with increasing motor density. This is in contrast to the transport behavior of multiple motors rigidly bound to a substrate. There, the motility is either insensitive to the motor density or shows negative interference at higher motor density, depending on the structure of the motors.
The cooperativity in transport driven by membrane-anchored motors can be explained as following: while stepping on a microtubule, membrane-anchored motors slip backwards in the viscous membrane, thus propelling the microtubule in the solution at a velocity, given by the difference of the motor stepping velocity and the slipping velocity. The motor stepping on the microtubule occurs at maximal stepping velocity because the load on the membrane-anchored motors is minute. Thus, the slipping velocity of membrane-anchored motors determines the microtubule gliding velocity. At steady state, the drag force on the microtubule in the solution is equal to the collective drag force on the membrane-anchored motors slipping in the viscous membrane. As a consequence, at low motor density, membrane-anchored motors slip back faster to balance the drag force of the microtubule in the solution. This results in a microtubule gliding velocity significantly lower than the maximal stepping velocity of the individual motors. In contrast, at high motor density, the microtubules are propelled faster with velocities equal to the maximal stepping velocity of individual motors. Because, in this case, the collective drag force on the motors even at very low slipping velocity, is large enough to balance the microtubule drag in the solution.
The theoretical model developed based on this explanation is in good agreement with the experimental data of gliding velocities at different motor densities. The model gives information about the distance that the diffusing motors can isotropically reach to bind to a microtubule, which for membrane-anchored kinesin-1 is ~0.3 µm, an order of magnitude higher as compared to rigidly bound motors, owing to the lateral mobility of motors on the membrane. In addition, the model can be used to predict the number of motors involved in transport of a microtubule based on its gliding velocity.
In the second part of the thesis, we investigated the effect of loose inter-motor coupling on the transport behavior of KIF16B, a recently discovered kinesin motor with an inherent lipid-binding domain. Recent studies based on cell biological and cell extract experiments, have postulated that cargo binding of KIF16B is required to activate and dimerize the motor, making it a superprocessive motor. Here, we demonstrate that recombinant full-length KIF16B is a dimer even in the absence of cargo or additional proteins. The KIF16B dimers are active and processive, which demonstrates that the motors are not auto-inhibited in our experiments. Thus, in cells and cell extracts Kif16B may be inhibited by additional factors, which are removed upon cargo binding. Single molecule analysis of KIF16B-GFP reveals that the motors are not superprocessive but exhibit a processivity similar to kinesin-1 indicating that additional factors are most likely necessary to achieve superprocessivity. Transport on membrane-anchored KIF16B motors exhibited a similar cooperative behavior as membrane-anchored kinesin-1 where the microtubule gliding velocity increased with increasing motor density.
Taken together, our results demonstrate that the loose coupling of motors via lipid bilayers provides flexibility to cytoskeletal transport systems and induces cooperativity in multi-motor transport. Moreover, our ‘membrane-anchored’ gliding motility assays can be used to study the effects of lipid diffusivity (e.g. the presence of lipid micro-domains and rafts), lipid composition, and adaptor proteins on the collective dynamics of different motors.
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Brunner, Christian J. "Cargo transport on engineered surfaces powered by molecular motors /." Zürich : ETH, 2007. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=17388.
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Pilizota, Teuta. "A programmable optical angle clamp for rotary molecular motors." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670185.
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Augulis, Ramūnas. "Molecular aggregates, dendrimers, and motors optical dynamics and control /." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 2008. http://irs.ub.rug.nl/ppn/.
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Wang, Lina. "Motors Involved in Neurofilament Transport." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1322540609.
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Craig, Erin Michelle 1980. "Models for Brownian and biomolecular motors." Thesis, University of Oregon, 2008. http://hdl.handle.net/1794/8565.
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xiv, 171 p. ; ill. (some col.) A print copy of this title is available through the UO Libraries. Search the library catalog for the location and call number.<br>Biological molecular motors, which use chemical energy from ATP hydrolysis to generate mechanical force, are involved in a variety of important mechanical processes in eukaryotic cells, such as intracellular transport, cell division and muscle contraction. These motors, which produce motion on the nanoscale, operate in the presence of substantial thermal noise.
In this dissertation, two approaches are used to model the physics of nanoscale motors: (1) A theoretically established type of Brownian motor called the "flashing ratchet" is studied. This motor transports diffusive particles in a preferred direction. (2) A coarse-grained mechanical model for the biological molecular motor myosin-V is developed, and used to study the role of Brownian diffusion, and the interaction between chemical and mechanical degrees of freedom, in the transport mechanism of this motor.
In chapter III, Brownian dynamics simulations and analytical calculations demonstrate that the average velocity of rigid chains of particles in a flashing ratchet reverses direction in response to changing the size of the chain or the temperature of the heat bath.
Recent studies have introduced policies for "closed-loop" control of a flashing ratchet, in which the system is controlled based on information about its internal state (such as the positional distribution of particles). In chapter IV, the effect of time delay on the implementation of closed-loop control of a flashing ratchet is investigated. For a large ensemble, a well-chosen delay time improves the ratchet performance (increasing the velocity) by synchronizing into a quasi-stable mode that takes advantage of the semi-deterministic nature of the time development of average quantities for a large ensemble. I
n chapter V, a coarse-grained mechanical model is presented for the transport mechanism of myosin-V, which walks along intracellular filaments. The model is well constrained by experimental data on the mechanical properties of myosin V and on the kinetic cycle. An experimentally motivated model for the intramolecular coordination of the motor's steps is proposed and tested.<br>Adviser: Heiner Linke
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Knight, Alexander Edward. "The diversity of myosin-like proteins." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337071.
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Malgaretti, Paolo. "Facing the environment: hydrodynamics and confinement modulate molecular motors dynamics." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/133402.
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In this thesis we characterize the behavior of molecular motors when the properties of the cytoplasm they displace through are not homogeneous or isotropic. Anisotropies in the cytoplasm can be induced, for example, by net fluxes that can be generated by the displacement of motors themselves as well by other mechanism such as remodeling of the overall cell shape. In the cytoplasm there are many molecules, proteins, vesicles and organelles in suspension. Such a crowded environment develop inhomogeneities in the local properties of the cytoplasm. The different length scales that characterize such inhomogeneities might led to different interplays according to the size of the cargo pulled by motors. For example, suspended particles whose size is much smaller than the cargo size will be experienced by the cargo as an enhancement in the effective viscosity. On the other hand, suspended particles of the same size or bigger than cargoes will develop local structures that affect the space the cargo can explore and will act like a porous medium.
In the first chapter we characterize the hydrodynamic coupling generated by an ensemble of molecular motors displacing along a filament. By numerical simulations we show how such a coupling develops. The hydrodynamic coupling between motor relies on the fluid flow generated by motors displacement. We discuss how the hydrodynamic coupling between motors depends upon the boundary conditions provided by different geometries.
Motors do not always displace in the same direction, rather cargoes pulled by teams of motors pulling on opposite directions has been observed to undergo a bidirectional motion where the cargo moves back and forth due to the reorganization of the force generated by the motors. In many cases the cargoes motors pull on are vesicles or membrane-embedded organelles. In these cases motors exert force on the cargo by pulling on molecular linkers embedded in the membrane that link the tail of the motors to the membrane. Therefore, the displacement of the linkers in the membrane will lead to a local flow of membrane that can lead to an overall coupling between motors that will sum up to the one generated by the displacement of the motors in the cytoplasm. In the second chapter we develop a coarse grained description of a team of motors pulling on opposite directions that are hydrodynamically coupled. Thanks to our coarse grained model we characterize the overall dynamics of the system and we discuss the peculiar features induced by the hydrodynamic coupling by comparing them against those obtained in the case of rigidly coupled motors.
In the third chapter we characterize the dynamics of a single molecular motor displacing in an inhomogeneous environment modeled as a varying section channel. In the limit in which the channel section is smoothly varying it is possible to reduce the overall dynamics to that of a particle moving in a 1D effective potential where the varying confinement enters as an entropic contribution to the overall potential. Using this framework we characterize the dynamics of molecular motors moving according to different schemes. The comparison between the results obtained with the different models allows us to distinguish between general behaviors and model dependent features.<br>El objetivo de esta tesis es la caracterización de la interacción entre la dinámica interna de los motores y el entorno en que los motores moleculares se mueven. Hemos caracterizado dos escenarios diferentes para los cuales las propiedades locales del fluido afectan significativamente a la dinámica general de los motores.
Como primer caso hemos estudiado la dinámica de varios motores moleculares que se desplazan a lo largo de un filamento común. Mientras se desplazan, los motores moleculares generan flujos citoplasmáticos locales que afectan el estado local del fluido. Por lo tanto la dinámica interna de los motores moleculares se ve afectada por el acoplamiento hidrodinámico entre los motores. Hemos caracterizado el acoplamiento hidrodinámico entre motores moleculares en dos escenarios diferentes. Por un lado hemos encontrado que el acoplamiento hidrodinámico entre motores proporcionados por el citoplasma puede afectar fuertemente a su velocidad global. Las variaciones locales en la densidad de motores pueden crecer y llevar a la formación de clusters que aceleran la velocidad de los motores y que conducen a la aparición de estructuras estables. Cuando varios motores están empujando una carga común, la naturaleza fluida de la membrana que envuelve la carga proporciona un acoplamiento hidrodinámico adicional entre los motores. En este escenario, hemos observado que el acoplamiento hidrodinámico entre los motores que tiran en direcciones opuestas, puede conducir a la ruptura de la simetría así como la biestabilidad incluso para tamaños de sistemas comparables con situaciones biológicas relevantes. Por lo tanto, las interacciones hidrodinámicas representan una alternativa para el control de la dinámica de la carga.
Como segundo caso hemos estudiado la dinámica de un motor molecular singlo en movimiento en un fluido intrínsecamente inhomogéneo en el cual, la inhomogeneidad del líquido se induce por la presencia de confinamientos geométricos. Si el espacio local disponible varia, surgen fuerzas adicionales de la naturaleza entrópica.
La interacción entre el movimiento a saltos del motor y la modulación en el confinamiento puede conducir a nuevos regímenes dinámicos, distintos de los que ocurren en el caso de partículas bajo fuerzas constantes o motores moleculares desplazando en un entorno homogéneo.
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Wickham, Shelley. "DNA origami : a substrate for the study of molecular motors." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.561126.
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DNA origami is a method for constructing 2-dimensional nanostructures with arbitrary shapes, by folding a long piece of viral genomic DNA into an extended pattern (Rothemund, 2006). In this thesis DNA origami nanostructures that in- corporate active transport are developed, by combining rectangular DNA origami tiles with either synthetic DNA motors, or the protein motor F1-ATPase. The transport of an autonomous, unidirectional, and processive 'burnt-bridges' DNA motor across an extended linear track anchored to a DNA origami tile is demonstrated. Ensemble fluorescence measurements are used to characterise motor transport, and are compared to a simple deterministic model of stepping. The motor moves 100 nm along a track at 0.1 nms-1 Atomic force microscopy (AFM) is used to study the transport of individual motor molecules along the track with single-step resolution. A DNA origami track for a 'two-foot' DNA motor is also developed, and is characterised by AFM and ensemble fluorescence measurements. The burnt-bridges DNA motor is then directed through a track network with either 1 or 3 bifurcations. Ensemble fluorescence measurements demonstrate that the path taken can be controlled by the addition of external control strands, or pre-programmed into the motor. A method for attaching the rotary motor protein F1-ATPase to DNA origami tiles is developed. Different bulk and single-molecule methods for demonstrat- ing protein binding are explored. Single-molecule observations of rotation of the protein motor on a DNA origami substrate are made, and are of equivalent data quality to existing techniques.
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Ahmadi, Aphrodite. "Hydrodynamics and rheology of mixtures of biopolymers and molecular motors." Related electronic resource: Current Research at SU : database of SU dissertations, recent titles available full text, 2008. http://wwwlib.umi.com/cr/syr/main.
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Curatolo, Agnese. "Collective behaviours in living systems : from bacteria to molecular motors." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC244/document.
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La première partie de ma thèse est consacrée à l’étude de l’auto-organisation de souches génétiquement modifiées de bactéries Escherichia coli. Ce projet, réalisé en collaboration avec des biologistes synthétiques de l’Université de Hong Kong, a pour objectif l’exploration et le décryptage d’un nouveau mécanisme d’auto-organisation dans des colonies bactériennes multi-espèces. Cela a été inspiré par la question fascinante de comment les écosystèmes bactériens comprenant plusieurs espèces de bactéries peuvent s’auto-organiser dans l’espace. En considérant des systèmes dans lesquels deux souches de bactéries régulent mutuellement leurs motilités, j’ai pu montrer que le contrôle de densité réciproque est une voie générique de formation de motifs: si deux souches tendent à faire augmenter mutuellement leur motilité (la souche A se déplace plus vite quand la souche B est présent, et vice versa), ils subissent un processus de formation de motifs conduisant à la démixtion entre les deux souches. Inversement, l’inhibition mutuelle de la motilité conduit à la formation de motifs avec colocalisation. Ces résultats ont étévalidés expérimentalement par nos collaborateurs biologistes. Par la suite, j’ai étendu mon étude à des systèmes composés de plus de deux espèces en interaction, trouvant des règles simples permettant de prédire l’auto-organisation spatiale d’un nombre arbitraire d’espèces dont la motilité est sous contrôle mutuel. Cette partie de ma thèse ouvre une nouvelle voie pour comprendre l’auto-organisation des colonies bactériennes avec des souches concurrentes, ce qui est une question importante pour comprendre la dynamique des biofilms ou des écosystèmes bactériens dans les sols. Le deuxième problème traité dans ma thèse est inspiré par le comportement collectif des moteurs moléculaires se déplaçant le long des microtubules dans le cytoplasme des cellules eucaryotes. Un modèle pertinent pour le mouvement des moteurs moléculaires est donné par un système paradigmatique de non-équilibre appelé Processus Asymmetrique d’Exclusion Simple, en anglais Asymmetric Simple Exclusion Process (ASEP). Dans ce modèle sur réseau unidimensionnel, les particules se déplacent dans les sites voisins vides à des taux constants, avec un biais gauche-droite qui déséquilibre le système.Lorsqu’il est connecté à ses extrémités à des réservoirs de particules, l’ASEP est un exemple prototypique de transitions de phase unidimensionnelles guidées par les conditions aux limites. Les exemples réalistes, cependant, impliquent rarement une seule voie:les microtubules sont constitués de plusieurs pistes de tubuline auxquelles les moteurs peuvent s’attacher. Dans ma thèse, j’explique comment on peut théoriquement prédire le comportement de phase de systèmes à plusieurs voies complexes, dans lesquels les particules peuvent également sauter entre des voies parallèles. En particulier, je montre que la transition de phase unidimensionnelle vue dans l’ASEP survit cette complexité supplémentaire mais implique de nouvelles caractéristiques telles que des courants transversaux stables non-nulles et une localisation de cisaillement<br>The first part of my thesis is devoted to studying the self-organization of engineered strains of run-and-tumble bacteria Escherichia coli. This project, carried out in collaboration with synthetic biologists at Hong Kong University, has as its objective the exploration and decipherment of a novel self-organization mechanism in multi-species bacterial colonies. This was inspired by the fascinating question of how bacterial ecosystems comprising several species of bacteria can self-organize in space. By considering systems in which two strains of bacteria mutually regulate their motilities, I was able to show that reciprocal density control is a generic pattern-formation pathway: if two strains tend tomutually enhance their motility (strain A moves faster when strain B is present, and conversely),they undergo a pattern formation process leading to demixing between the two strains. Conversely, mutual inhibition of motility leads to pattern formation with colocalization. These results were validated experimentally by our biologist collaborators. Subsequently, I extended my study to systems composed of more than two interacting species, finding simple rules that can predict the spatial self-organization of an arbitrary number of species whose motility is under mutual control. This part of my thesis opens up a new route to understand the self-organization of bacterial colonies with competing strains, which is an important question to understand the dynamics of biofilms or bacterial ecosystems in soils.The second problem treated in my thesis is inspired by the collective behaviour ofmolecular motorsmoving along microtubules in the cytoplasm of eukaryotic cells. A relevant model for the molecularmotors’ motion is given by a paradigmatic non-equilibrium system called Asymmetric Simple Exclusion Process (ASEP). In this one-dimensional lattice- based model, particles hop on empty neighboring sites at constant rates, with a leftright bias that drives the systemout of equilibrium. When connected at its ends to particle reservoirs, the ASEP is a prototypical example of one-dimensional boundary driven phase transitions. Realistic examples, however, seldom involve only one lane: microtubules are made of several tubulin tracks to which the motors can attach. In my thesis, I explained how one can theoretically predict the phase behaviour of complex multilane systems, in which particles can also hop between parallel lanes. In particular, I showed that the onedimensional phase transition seen in the ASEP survives this additional complexity but involves new features such as non-zero steady transverse currents and shear localization
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Clayton, Joseph Emerson. "Barcoding the actin track: Differential regulation of myosin motors by tropomyosin." ScholarWorks @ UVM, 2016. http://scholarworks.uvm.edu/graddis/638.
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Myosins and tropomyosins represent two types of actin filament-associated proteins that often work together in contractile and motile processes in the cell. While the role of thin filament troponin-tropomyosin complexes in regulating striated muscle myosin II is well characterized, the role of tropomyosins in non-muscle myosin regulation is not well understood. Fission yeast has recently proved to be a useful model with which to study regulation of myosin motors by tropomyosin owing to its tractable genetics, well-defined actin cytoskeleton, and established actin biochemistry.
A hallmark of type V myosins is their processivity -- the ability to take multiple steps along actin filaments without dissociating. However, the fission yeast type V myosin (Myo52) is a nonprocessive motor whose activity is enhanced by the sole fission yeast tropomyosin (Cdc8). The molecular mechanism and physiological relevance of tropomyosin-mediated regulation of Myo52 transport was investigated using a combination of in vitro and in vivo approaches. Single molecules of Myo52, visualized by total internal reflection fluorescence microscopy, moved processively only when Cdc8 was present on actin filaments. Small ensembles of Myo52 bound to a quantum dot, mimicking the number of motors bound to physiological cargo, also required Cdc8 for continuous motion. Although a truncated form of Myo52 that lacked a cargo-binding domain failed to support function in vivo, it still underwent actin-dependent movement to polarized growth sites. This result suggests that truncated Myo52 lacking cargo, or single molecules of wild-type Myo52 with small cargoes, can undergo processive movement along actin-Cdc8 cables in vivo. These findings outline a mechanism by which tropomyosin facilitates sorting of transport to specific actin tracks within the cell by switching on myosin processivity.
To understand the broader implications of actomyosin regulation by tropomyosin we examined the role of two mammalian tropomyosins (Tpm3.1 and Tpm4.2) recently implicated in cancer cell proliferation and metastasis. As previously observed with Cdc8, Tpm3.1 and Tpm4.2 isoforms significantly enhance non-muscle myosin II (Myo2). Additionally, the mammalian tropomyosins enable Myo52 processive movement along actin tracks. In contrast to the positive regulation of Myo2 and Myo52, Cdc8 and the mammalian tropomyosins potently inhibit skeletal muscle myosin II, while having negligible effects on the highly processive mammalian myosin-Va. Thus, different motor outputs favoring functional specification within the same myosin class are possible in the presence of certain tropomyosins. In support of a conserved role for certain tropomyosins in regulating non-muscle actomyosin structures, Tpm3.1 rescued normal contractile ring dynamics, cytokinesis, and fission yeast cell growth in the absence of functional Cdc8. This work has broad implications with regard to regulation of non-muscle and muscle actomyosin function in complex cellular environments such as developing muscle tissue and metastatic cancer cells.
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Lichtenthäler, Daniel Gomes. "Movimento bidirecional no transporte intracelular mediado por motores moleculares." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/43/43134/tde-27022008-142311/.
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Neste trabalho apresentamos um modelo teórico que busca descrever aspectos do movimento bidirecional apresentado por objetos intracelulares (vesículas, organelas, vírus etc, aos quais iremos nos referir simplesmente como (\"vesículas\"), observado, sobretudo em experimentos in vivo. Este movimento nao-difusivo e caracterizado por inversões rápidas em sua direção e é capaz de gerar gradientes de concentração do objeto transportado. Os fenômenos de transporte intracelular são sabidamente mediados por proteínas motoras (como as kinesinas e dinenas) cujo movimento unidirecional sobre _lamentos protéicos e bem caracterizado (kinesinas se movem em direção a extremidade mais enquanto as dinenas se movem em direção a extremidade-menos dos microtúbulos) e é normalmente entendido através de modelos estocásticos que descrevem o comportamento de uma partícula browniana na presença de um potencial assimétrico que varia no tempo (ver Astumian [26], Adjari e Prost [22], Magnasco [23]). Mais recentemente, surgiram na literatura trabalhos que tentam descrever o movimento de partículas motoras interagentes, uma vez que se percebeu que efeitos coletivos que surgem nestas situações podem ser relevantes para os fenômenos de transporte sobre microtúbulos. Uma abordagem para a descrição do comportamento destes sistemas de partículas motoras interagentes é aquela baseada nos modelos para os sistemas difusivos dirigidos\". Em particular, a versão contínua dos modelos do tipo totally asymmetric exclusion processes\" (TASEP) e asymmetric exclusion processes\" (ASEP) tem sido utilizada para o estudo do comportamento da densidade de motores sobre os microtúbulos, através da analise de soluções estacionarias da equação de Burgers correspondente (Parmeggiani et al. [33]). Até agora, entretanto, não existem na literatura tentativas de abordar, com estes modelos, o transporte bidirecional de vesículas mediado por estes motores interagentes. A idéia que apresentamos aqui é associar este estranho tipo de movimento ao movimento de ondas de choque presentes nas soluções transientes da equa_c~ao de Burgers para algumas condições iniciais. Deste modo, as vesículas acompanhando (\"surfando\") os choques fariam o papel de suas correspondentes microscópicas partículas de segunda classe\", introduzidas h_a um bom tempo na literatura [36], [37], [38] para o estudo da dinâmica microscópica dos choques que estão presentes também na versão discreta dos modelos TASEP e ASEP. Neste sentido, é natural que as condições iniciais consideradas, que seriam perturbações no estado estacionário das partículas, possam ser causadas, no sistema real, pela própria interação com a vesícula. É o caso, portanto, de se propor que a geometria deste objeto tenha um papel importante na determinação da direcional de seu próprio movimento no meio intracelular. Esta parece ser, por exemplo, uma alternativa interessante para explicar aspectos do movimento de vírus no interior das células.<br>In this work we present a theoretical model to describe aspects of the bidirectional movement performed by intracellular structures (vesicles, organelles, viruses etc, to which we refer here simply as \"vesicles\"), observed essentially at in vivo experiments. This nondifusive movement is characterized by rapid inversions in direction and is capable of creating concentration gradients of the transported cargo. The phenomenon of intracellular transport is known to be mediated by motor proteins (such as kinesins and dyneins) whose own unidirectional motion along protein laments is well characterized (kinesins moves to the plus-end direction while dyneins moves to the minus-end direction of the microtubules) and is usually modeled by a stochastic dynamics describing the behavior of a Brownian particle in the presence of a time dependent asymmetrical potential held (see Astumian [26], Adjari and Prost [22], Magnasco [23]). More recently, it appeared in the literature works attempting to describe the movement of interacting motor proteins, since it was realized that collective e_ects emerging from this situation may be relevant to the transport phenomena along microtubules. An approach to describe the behavior of such interacting motor particles is based on existing models for \\driven di_usive systems\". In particular, the continuum versions of the totally asymmetric exclusion processes\" (TASEP) or the asymmetric exclusion processes\" (ASEP) have been used to study the behavior of motors density along microtubules by analyzing the steady state solutions to the corresponding Burgers equation (Parmeggiani et al. [33]). Up to now, however, there are no attempts in the literature to approach in this context the questions related to the bidirecionality of vesicles transported by these interacting motors. The idea we present here is to associate this odd movement to the movement of shock waves presented by the transient solutions of Burgers equation for certain initial conditions. Accordingly, the vesicles accompanying (sur_ng) the shocks fronts would play the role of their microscopic analogous \\particles of second class\" introduced long ago in the literature [36], [37], [38] to study the kinetics of the shocks that are also present in the discrete versions of the TASEP and ASEP. In this regard, it is natural to think that the considered initial conditions, namely perturbations to the motor density with respect to a steady state, can be created in the real systems simply by the interaction with the vesicle. It might then be the case also to propose that the geometry of the vesicle plays an important role to direct its own movement within intracellular environment. This seems to be, for example, an attractive alternative for explaining aspects of virus movement inside the cell.
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Hartman, Adam Z. "Effects of nanoconfinement on molecular motors : collective kinesin behavior, external modulation, and applications to molecular transport." View abstract/electronic edition; access limited to Brown University users, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3318324.
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Chandrashaker, Akhila. "Systems analysis of early endosome motility through identification of molecular motors." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2010. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-61594.
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Endocytosis is an evolutionary conserved process of internalization of cargo from the extracellular environment, be they ligands, nutritional and signaling or pathogens into cells. Following their entry, cargo is received into vesiculo-tubular network of early endosomal compartments from where they are sorted and routed to appropriate cellular destinations through transport along the endocytic network. Recycling cargo is sorted away from other cargo resident in early endosomes through tubulation resulting in fission of recycling vesicles, while those to be degraded are progressively concentrated in early endosomes to be degraded in lysosomes.
Early endosomes are dynamic organelles that have been shown to move centripetally following the internalization of cargo into at the cell periphery. Their motility from the cell periphery to the juxtanuclear location of the cell involves convoluted trajectories that include directed motility, bi-directional switches, saltatory behavior and stalls. This complex motility presumably contributes toward the cargo sorting, duration of cargo residence and spatio-temporal signaling by early endosomes. How the different regimes of motility, and nature and number of molecular motors involved in early endosome motility contribute toward endosome function is not understood.
The aim of this study was to probe into the regulation of endosome motility and understand how transport organizes early endosome network. Towards this end, live cell time-lapse movies of Rab5 endosomes were analyzed to derive motility properties contributing to organization of early endosomes. Consistent and significant bias toward the cell centre (minus end motility) in kinetic parameters such as speed, displacement and duration of motility contribute to centripetal flux of Rab5 early endosomes.
A phenomenological property of early endosome motility is its saltatory behavior that produces saturation curves in Mean Square Displacement (MSD) plots. This phase of motility is descriptive, with no understanding of its mechanism or function. Live cell candidate RNAi screen and cytoskeletal perturbation analysis were performed to identify molecules regulating saltatory motility. To this end, cellular microtubule perturbation and RNAi knock down of several Kinesin motor candidates showed a loss in saturation behavior. Potential candidates identified have to be tested for their effect on endosome function through cargo sorting and kinetic assays to gain insights into the role of saltatory motility in endosome function.
Molecular motors mediate Rab5 motility. Therefore, understanding regulation of motility requires identifying number and nature of molecular motors involved in their transport. Towards this end, a functional cargo (LDL) degradation RNAi screen targeting molecular motors was performed. The Ambion Select technology was used with 3 siRNAs targeting every gene in the library. Analysis of screen produced by lack of phenotype consistency between the multiple siRNAs targeting the same gene. Hence, a search for technology with better target specificity was initiated. Technologies tested were Ambion Select, Ambion Silencer Select, Dharmacon ON-TARGET Plus, esiRNA and Invitrogen Stealth. Invitrogen Stealth technology was found to produce the least off-targets and was most specific in terms of consistency of phenotypes produced by multiple siRNAs silencing the same target gene. Assay conditions were also found to influence the silencing specificities to a significant extent. Hence, a systematic assay optimization exercise was performed in terms of the concentration of siRNA used for transfection and time window of assay to maximize specificity of siRNA silencing. Insights obtained from methodologies developed herein not only provide invaluable guidelines in choosing RNAi commercial libraries for screens, but also underscore the importance of establishing optimal assay conditions to minimize off-targets and improve specificity of silencing target genes.
The motor screen was repeated with RNAi library from Invitrogen Stealth. Several potentially interesting candidates have been identified. Also, correlation analyses of phenotypes produced in the screen have indicated toward potential regulatory motor complexes, all of which await biochemical validation.
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Huber, Ludwig Alexander [Verfasser], and Henry [Akademischer Betreuer] Dube. "Indigoid molecular motors and switches / Ludwig Alexander Huber ; Betreuer: Henry Dube." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/123320050X/34.
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Lin, Ying. "Progress toward synthetic molecular motors : directed single bond rotation in a prototypical biaryl lactone system /." view abstract or download file of text, 2007. http://proquest.umi.com/pqdweb?did=1324377621&sid=1&Fmt=2&clientId=11238&RQT=309&VName=PQD.
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Thesis (Ph. D.)--University of Oregon, 2007.<br>Typescript. Includes vita and abstract. Includes bibliographical references (leaves 109-124). Also available for download via the World Wide Web; free to University of Oregon users.
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Jannasch, Anita. "High performance photonic probes and applications of optical tweezers to molecular motors." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-103696.
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Optical tweezers are a sensitive position and force transducer widely employed in physics and biology. In a focussed laser, forces due to radiation pressure enable to trap and manipulate small dielectric particles used as probes for various experiments. For sensitive biophysical measurements, microspheres are often used as a handle for the molecule of interest. The force range of optical traps well covers the piconewton forces generated by individual biomolecules such as kinesin molecular motors. However, cellular processes are often driven by ensembles of molecular machines generating forces exceeding a nanonewton and thus the capabilities of optical tweezers. In this thesis I focused, fifirst, on extending the force range of optical tweezers by improving the trapping e fficiency of the probes and, second, on applying the optical tweezers technology to understand the mechanics of molecular motors. I designed and fabricated photonically-structured probes: Anti-reflection-coated, high-refractive-index, core-shell particles composed of titania. With these probes, I significantly increased the maximum optical force beyond a nanonewton. These particles open up new research possibilities in both biology and physics, for example, to measure hydrodynamic resonances associated with the colored nature of the noise of Brownian motion. With respect to biophysical applications, I used the optical tweezers to study the mechanics of single kinesin-8. Kinesin-8 has been shown to be a very processive, plus-end directed microtubule depolymerase. The underlying mechanism for the high processivity and how stepping is affected by force is unclear. Therefore, I tracked the motion of yeast (Kip3) and human (Kif18A) kinesin-8s with high precision under varying loads. We found that kinesin-8 is a low-force motor protein, which stalled at loads of only 1 pN. In addition, we discovered a force-induced stick-slip motion, which may be an adaptation for the high processivity. Further improvement in optical tweezers probes and the instrument will broaden the scope of feasible optical trapping experiments in the future.
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Lee, Huan Fang. "The role of microtubules and their associated molecular motors in autophagosome biogenesis." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708628.
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Oruganti, Baswanth. "Computational Design of Molecular Motors and Excited-State Studies of Organic Chromophores." Doctoral thesis, Linköpings universitet, Bioinformatik, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-132611.
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This thesis presents computational quantum chemical studies of molecular motors and excited electronic states of organic chromophores. The first and major part of the thesis is concerned with the design of light-driven rotary molecular motors. These are molecules that absorb light energy and convert it into 360° unidirectional rotary motion around a double bond connecting two molecular halves. In order to facilitate potential applications of molecular motors in nanotechnology, such as in molecular transport or in development of materials with photo-controllable properties, it is critical to optimize the rates and efficiencies of the chemical reactions that produce the rotary motion. To this end, computational methods are in this thesis used to study two different classes of molecular motors. The first class encompasses the sterically overcrowded alkenes developed by Ben Feringa, co-recipient of the 2016 Nobel Prize in Chemistry. The rotary cycles of these motors involve two photoisomerization and two thermal isomerization steps, where the latter are the ones that limit the attainable rotational frequencies. In the thesis, several new motors of this type are proposed by identifying steric, electronic and conformational approaches to accelerate the thermal isomerizations. The second class contains motors that incorporate a protonated Schiff base and are capable to achieve higher photoisomerization rates than overcrowded alkene-based motors. In the thesis, a new motor of this type is proposed that produces unidirectional rotary motion by means of two photochemical steps alone. Also, this motor lacks both a stereocenter and helical motifs, which are key features of almost all synthetic rotary motors developed to date. The second part of the thesis focuses on the design and assessment of composite computational procedures for modeling excited electronic states of organic chromophores. In particular, emphasis is put on developing procedures that facilitate the calculations of accurate 0−0 excitation energies of such compounds in a cost-effective way by combining quantum chemical methods with different accuracies.
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Hill, David Brooks. "Changes in the number of molecular motors driving vesicle transport in PC12 /." Electronic thesis, 2003. http://dspace.zsr.wfu.edu/jspui/handle/10339/206.
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Schiel, Philippe. "Study of light-triggered molecular motors self-assembled at surfaces and interfaces." Electronic Thesis or Diss., Strasbourg, 2024. https://publication-theses.unistra.fr/restreint/theses_doctorat/2024/Schiel_Philippe_2024_ED222.pdf.
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L'intégration de moteurs moléculaires aux interfaces permet de former des structures assemblées hautement organisées qui utilisent leur mouvement moléculaire afin d'obtenir des surfaces sensibles aux stimuli. Dans cette thèse, nous avons principalement étudié l'impact de l'irradiation par la lumière UV sur les moteurs moléculaires amphiphiles à l'interface dynamique air-eau et sur les moteurs moléculaires ancrés à la surface sur des interfaces solides. Nous montrons que la rotation des moteurs amphiphiles dans les monocouches de Langmuir peut induire d'importants changements dans la compressibilité et la structuration supramoléculaire, conduisant à un premier exemple de processus de polymérisation supramoléculaire induit par le mouvement aux interfaces. Nous rapportons également une première étude de moteurs ancrés à la surface par spectroscopie de force sur une seule molécule, montrant que la rotation des moteurs peut être utilisée pour modifier les propriétés mécaniques et conformationnelles des chaînes polymères attachées. De plus, nous décrivons un système basé sur des moteurs ancrés à la surface qui peut être utilisé pour imiter le mouvement induit par un moteur biologique. Enfin, nous avons cherché à étudier une application concrète pour la rotation des moteurs moléculaires en les intégrant dans des membranes d'ultrafiltration disponibles commercialement<br>The integration of molecular motors at interfaces allows to form highly organised assembled structures that use their molecular motion in order to obtain stimuli-responsive surfaces. In this thesis, we mainly studied the impact of UV light irradiation on amphiphilic molecular motors at the dynamic air-water interface and on surface-anchored molecular motors at solid interfaces. We show that the rotation of amphiphilic motors in Langmuir monolayers can induce large changes in the compressibility and the supramolecular structuration, leading to a first example of a motion induced supramolecular polymerisation process at interfaces. Herein, we also report a first study on surface-anchored motors by single molecule force spectroscopy, showing that the rotation of motors can be used to change the mechanical and conformational properties of the attached polymer chains. Further, we describe a system based on surface-anchored motors that can be used in mimicking the motion induced by a biological motor. Finally, we aimed to investigate a concrete application for the rotation of molecular motors by integrating them in commercially available ultrafiltration membranes
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Hernandez-Lopez, Rogelio Antonio. "Mechanistic Studies of the Microtubule-Based Motors Dynein and Kinesin-8." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467496.
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The precise delivery and organization of intracellular factors in space and time relies on a set of molecules that move along and regulate the dynamics of cytoskeletal filaments. The two families of microtubule-based motors-- dyneins and kinesins-- power vital biological processes such as intracellular transport, chromosome segregation and more broadly cell-cell communication and cell polarization. Despite their role in such diverse activities, their molecular mechanisms remain poorly understood. Combining biochemistry, cryo-electron microscopy, molecular dynamics simulations and single molecule biophysics, we provide novel insights into the mechanistic basis of how dynein and kinesin-8 interact with microtubules (MTs) to regulate their function.
Cytoplasmic dynein is a homodimer that moves for long distances along MTs without dissociating, a property known as processivity. Its movement requires coupling cycles of ATP binding and hydrolysis to changes in affinity for its track. Intriguingly, the main site of ATP hydrolysis in the motor is separated from the microtubule binding domain (MTBD) by 25 nm. How do these sites communicate with each other? What are the changes responsible for modulating the affinity between the motor and its track during dynein’s mechanochemical cycle? Furthermore, it has been shown that dynein’s stepping behavior is highly variable. Dynein walks by taking a broad distribution of step sizes; some of its steps are sideways and some are backwards. Is dynein’s stepping behavior dictated by the motor’s ATPase activity or dynein’s affinity for MTs? To address these important questions, first, we solved a cryo-EM reconstruction of dynein’s MTBD bound to the MT. We found that upon MT binding, dynein’s MTBD undergoes a large conformational change underlying changes in its affinity for MTs. Our structural model suggested specific negatively charged residues within the MTBD that tune dynein’s affinity for MTs. We mutated these residues to alanine and show a dramatic increase in dynein’s MT binding affinity resulting in enhanced (~5-6 fold) motor processivity. These mutants provide us with a tool to explore the role of MT-binding affinity in dynein’s stepping behavior. We characterized, using single molecule experiments, the stepping pattern of the high MT binding affinity dyneins. We found that an increased MT-binding affinity reduces dynein’s stepping rate and impairs the coupling between ATPase activity and stepping. Together, our results provide a model for how dynein has evolved a finely tuned mechanism that allows its MTBD to communicate MT-binding to its motor domain. This mechanism also regulates dyneins’s affinity for the MT and motor’s processivity.
We then sought to understand the unique functional properties of kinesin-8. Unlike other kinesins that have the ability to either move along microtubules or regulate the dynamics of MT-ends, kinesin-8s can do both. Kip3, the budding yeast kinesin-8, is a highly processive motor capable of dwelling at the MT plus-end and it is a MT depolymerase. Given the highly conserved sequence and structure of kinesin’s motor domain, how is that Kip3 can perform these two distinct functions? Does Kip3 interact with the MT-lattice in the same manner than that at the MT-end? We characterized, structurally, how Kip3 binds to microtubules that mimic the MT-lattice and the MT-end. We have identified and tested specific residues within Kip3 that are responsible for Kip3’s processivity, MT-end dwelling and depolymerization activity.<br>Chemical Physics
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Bierbaum, Veronika. "Chemomechanical coupling and motor cycles of the molecular motor myosin V." Phd thesis, Universität Potsdam, 2011. http://opus.kobv.de/ubp/volltexte/2011/5361/.
Full textAbstract:
In the living cell, the organization of the complex internal structure relies to a large extent on molecular motors. Molecular motors are proteins that are able to convert chemical energy from the hydrolysis of adenosine triphosphate (ATP) into mechanical work. Being about 10 to 100 nanometers in size, the molecules act on a length scale, for which thermal collisions have a considerable impact onto their motion. In this way, they constitute paradigmatic examples of thermodynamic machines out of equilibrium.
This study develops a theoretical description for the energy conversion by the molecular motor myosin V, using many different aspects of theoretical physics. Myosin V has been studied extensively in both bulk and single molecule experiments. Its stepping velocity has been characterized as a function of external control parameters such as nucleotide concentration and applied forces. In addition, numerous kinetic rates involved in the enzymatic reaction of the molecule have been determined. For forces that exceed the stall force of the motor, myosin V exhibits a 'ratcheting' behaviour: For loads in the direction of forward stepping, the velocity depends on the concentration of ATP, while for backward loads there is no such influence.
Based on the chemical states of the motor, we construct a general network theory that incorporates experimental observations about the stepping behaviour of myosin V. The motor's motion is captured through the network description supplemented by a Markov process to describe the motor dynamics. This approach has the advantage of directly addressing the chemical kinetics of the molecule, and treating the mechanical and chemical processes on equal grounds. We utilize constraints arising from nonequilibrium thermodynamics to determine motor parameters and demonstrate that the motor behaviour is governed by several chemomechanical motor cycles. In addition, we investigate the functional dependence of stepping rates on force by deducing the motor's response to external loads via an appropriate Fokker-Planck equation. For substall forces, the dominant pathway of the motor network is profoundly different from the one for superstall forces, which leads to a stepping behaviour that is in agreement with the experimental observations.
The extension of our analysis to Markov processes with absorbing boundaries allows for the calculation of the motor's dwell time distributions. These reveal aspects of the coordination of the motor's heads and contain direct information about the backsteps of the motor.
Our theory provides a unified description for the myosin V motor as studied in single motor experiments.<br>Die hier vorgelegte Arbeit entwickelt unter Verwendung vieler verschiedener Aspekte der statistischen Physik eine Theorie der chemomechanischen Kopplung für den Energieumsatz des molekularen Motors Myosin V. Das Myosin V ist sowohl in chemokinetischen wie in Einzelmolekülexperimenten grundlegend untersucht worden. Seine Schrittgeschwindigkeit ist in Abhängigkeit verschiedener externer Parameter, wie der Nukleotidkonzentration und einer äußeren Kraft, experimentell bestimmt. Darüber hinaus ist eine große Anzahl verschiedener chemokinetischer Raten, die an der enzymatischen Reaktion des Moleküls beteiligt sind, quantitativ erfasst. Unter der Wirkung externer Kräfte, die seine Anhaltekraft überschreiten, verhält sich der Motor wie eine Ratsche: Für Kräfte, die entlang der Schrittbewegung des Motors wirken, hängt seine Geschwindigkeit von der ATP-Konzentration ab, für rückwärts angreifende Kräfte jedoch ist die Bewegung des Motors unabhängig von ATP.
Auf der Grundlage der chemischen Zustände des Motors wird eine Netzwerktheorie aufgebaut, die die experimentellen Beobachtungen
des Schrittverhaltens für Myosin V einschließt. Diese Netzwerkbeschreibung dient als Grundlage für einen Markovprozess, der die Dynamik des Motors beschreibt. Die Verwendung diskreter Zustände bietet den Vorteil der direkten Erfassung der chemischen Kinetik des Moleküls. Darüber hinaus werden chemische und mechanische Eigenschaften des Motors in gleichem Maße im Modell berücksichtigt. Durch die Erfassung der Enzymkinetik mittels eines stochastischen Prozesses lässt sich die Motordynamik mit Hilfe des stationären Zustands der Netzwerkdarstellung beschreiben. Um diesen zu bestimmen, verwenden wir eine graphentheoretische Methode, die auf Kirchhoff zurückgreift.
Wir zeigen in Einklang mit den Gesetzen der Thermodynamik für Nichtgleichgewichtssysteme, dass das Schrittverhalten des Motors von mehreren chemomechanischen Zyklen beeinflusst wird. Weiterhin untersuchen wir das funktionale Verhalten mechanischer Schrittraten in Abhängigkeit der äußeren Kraft unter Verwendung einer geeigneten Fokker-Planck-Gleichung. Hierfür wird auf die Theorie einer kontinuierlichen Beschreibung von molekularen Methoden zurückgegriffen.
Wir berechnen Größen wie die mittlere Schrittgeschwindigkeit, das Verhältnis von Vorwärts- und Rückwärtsschritten, und die Lauflänge des Motors in Abhängigkeit einer äußeren angreifenden Kraft sowie der Nukleotidkonzentration, und vergleichen diese mit experimentellen Daten.
Für Kräfte, die kleiner als die Anhaltekraft des Motors sind, unterscheidet sich der chemomechanische Zyklus grundlegend von demjenigen, der für große Kräfte dominiert. Diese Eigenschaft resultiert in einem Schrittverhalten, das mit den experimentellen Beobachtungen übereinstimmt. Es ermöglicht weiterhin die Zerlegung des Netzwerks in einzelne Zyklen, die die Bewegung des Motors für verschiedene Bereiche externer Kräfte erfassen.
Durch die Erweiterung unseres Modells auf Markovprozesse mit absorbierenden
Zuständen können so die Wartezeitenverteilungen für einzelne Zyklen des Motors analytisch berechnet werden.
Sie erteilen Aufschluss über die Koordination des Motors und enthalten zudem direkte Informationen über seine Rückwärtsschritte, die experimentell nicht erfasst sind. Für das gesamte Netzwerk werden die Wartezeitenverteilungen mit Hilfe eines Gillespie-Algorithmus bestimmt. Unsere Theorie liefert eine einheitliche Beschreibung der Eigenschaften von Myosin V, die in Einzelmolekülexperimenten erfasst werden können.
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Dahl, Bartholomew James. "The design and synthesis of prototypical artificial molecular motors : studies of directed bond rotation in chiral biaryls /." view abstract or download file of text, 2007. http://proquest.umi.com/pqdweb?did=1288652831&sid=3&Fmt=2&clientId=11238&RQT=309&VName=PQD.
Full textAbstract:
Thesis (Ph. D.)--University of Oregon, 2007.<br>Typescript. Includes vita and abstract. Includes bibliographical references (leaves 151-165). Also available for download via the World Wide Web; free to University of Oregon users.
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Ziebert, Falko. "Modeling pattern formation in biopolymer systems induced by reaction kinetics and molecular motors." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=981270492.
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Berger, Florian [Verfasser], and Reinhard [Akademischer Betreuer] Lipowsky. "Different modes of cooperative transport by molecular motors / Florian Berger. Betreuer: Reinhard Lipowsky." Potsdam : Universitätsbibliothek der Universität Potsdam, 2012. http://d-nb.info/102441311X/34.
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Clemmens, John Scott. "Engineering surfaces for directed motion of motor proteins : building a molecular shuttle system /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/8024.
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Sasai, Masaki, Tomoki P. Terada, and Mitsunori Takano. "Unidirectional Brownian motion observed in an in silico single molecule experiment of an actomyosin motor." National Academy of Sciences, 2010. http://hdl.handle.net/2237/20619.
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Lombardo, Andrew Thomas. "Cargo Transport By Myosin Va Molecular Motors Within Three-Dimensional In Vitro Models Of The Intracellular Actin Cytoskeletal Network." ScholarWorks @ UVM, 2018. https://scholarworks.uvm.edu/graddis/860.
Full textAbstract:
Intracellular cargo transport involves the movement of critical cellular components (e.g. vesicles, organelles, mRNA, chromosomes) along cytoskeletal tracks by tiny molecular motors. Myosin Va motors have been demonstrated to play a vital role in the transport of cargos destined for the cell membrane by navigating their cargos through the three-dimensional actin networks of the cell. Transport of cargo through these networks presents many challenges, including directional and physical obstacles which teams of myosin Va-bound to a single cargo must overcome. Specifically, myosin Va motors are presented with numerous actin-actin intersections and dense networks of filaments which can act as a physical barrier to transport. Due to the complexities of studying myosin Va cargo transport in cells, much effort has been focused on the in vitro observation and analysis of myosin Va transport along single actin filaments or simple actin cytoskeletal models. However, these model systems often rely on non-physiological cargos (e.g. beads, quantum dots) and two-dimensional arrangements of actin attached to glass surfaces. Interestingly, a disconnect exists between the transport of cargo on these simple model systems and studies of myosin Va transport on suspended 3D actin arrangements or cellular networks which show longer run lengths, increased velocities, and straighter, more directed trajectories. One solution to this discrepancy is that the cell may use the fluidity of the cargo surface, the recruitment of myosin Va motor teams, and the 3D geometry of the actin, to finely tune the transport of intracellular cargo depending on cellular need.
To understand how myosin Va motors transport their cargo through 3D networks of actin, we investigated myosin Va motor ensembles transporting fluorescent 350 nm lipid-bilayer cargo through arrangements of suspended 3D actin filaments. This was accomplished using single molecule fluorescent imaging, three-dimensional super resolution Stochastic Optical Reconstruction Microscopy (STORM), optical tweezers, and in silico modeling. We found that when moving along 3D actin filaments, myosin motors could be recruited from across the fluid lipid cargo’s surface to the filaments which enabled dynamic teams to be formed and explore the full actin filaments binding landscape. When navigating 3D actin-actin intersections these teams capable of maneuvering their cargo through the intersection in a way that encouraged the vesicles to continue straight rather than switch filaments and turn at the intersection. We hypothesized that this finding may be the source of the relatively straight directed runs by myosin Va-bound cargo observed in living cells. To test this, we designed 3D actin networks where the vesicles interacted with 2-6 actin filaments simultaneously. Actin forms polarized filaments, which, in cells, generally have their plus-ends facing the exterior of the cell; the same direction in which myosin Va walks. We found that to maintain straight directed trajectories and not become stationary within the network, vesicles needed to move along filaments with a bias in their polarity. This allows for cargo-bound motors to align their motion along the polarized networks and produced productive motion despite physical and directional obstacles. Together this work demonstrates the physical properties of the cargo, the geometric arrangement of the actin, and the mechanical properties of the motor are all critical aspects of a robust myosin Va transport system.