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1
Hyvönen, M. (Marja). "Molecular dynamics simulations on phospholipid membranes." Doctoral thesis, University of Oulu, 2001. http://urn.fi/urn:isbn:9514259432.
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Abstract
Phospholipids are the main components of cell membranes, lipoproteins and other
membrane structures in living organisms. Properties of lipid molecules are important to the
overall behaviour and interactions of membranes. Furthermore, characteristics of the
biological membranes act as important regulators of membrane functions. Molecular dynamics
(MD) simulations were applied in this thesis to study properties of biological membranes. A
certain degree of acyl chain polyunsaturation is essential for the proper functioning of
membranes, but earlier MD simulations had not addressed the effects of polyunsaturation.
Therefore a solvated all-atom bilayer model consisting of diunsaturated
1-palmitoyl-2-linoleoyl-3-phosphatidylcholine (PLPC) molecules was simulated. The analysis
of the simulation data was focused on the effects of double bonds on a membrane structure.
Self-organising neural networks were applied to the analysis of the
conformational data from the 1-ns simulation of PLPC membrane. Mapping of 1.44 million
molecular conformations to a two-dimensional array of neurons revealed, without human
intervention or requirement of a priori knowledge, the main
conformational features. This method provides a powerful tool for gaining insight into the
main molecular conformations of any simulated molecular assembly.
Furthermore, an application of MD simulations in the comparative analysis of
the effects of lipid hydrolysis products on the membrane structure was introduced. The
hydrolysis products of the phospholipase A2
(PLA2) enzyme are known to have a role in a variety of physiological
processes and the membrane itself acts as an important regulator of this enzyme. The
simulations revealed differences in the bilayer properties between the original and
hydrolysed phospholipid membranes. This study provides further evidence that MD simulations
on biomembranes are able to provide information on the properties of biologically and
biochemically important lipid systems at the molecular level.
2
Chen, Wei. "Molecular dynamics simulations of binding, unfolding, and global conformational changes of signaling and adhesion molecules." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/28118.
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Thesis (M. S.)--Mechanical Engineering, Georgia Institute of Technology, 2009.<br>Committee Chair: Zhu, Cheng; Committee Member: Harvey, Stephen; Committee Member: Hud, Nicholas; Committee Member: Zamir, Evan; Committee Member: Zhu, Ting.
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Atzori, Alessio. "Conformational analysis of peptides and proteins for drug design using molecular simulations." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/conformational-analysis-of-peptides-and-proteins-for-drug-design-using-molecular-simulations(050ba296-a4c4-4a5b-87bf-66d90f7ddc5a).html.
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The intrinsic plasticity of biological systems provides opportunities for rational design of selective and potent ligands. Increasingly, computational methods are being applied to predict biomolecular flexibility. However, the motions involved in these processes can be large and occur on time scales generally difficult to achieve with standard simulation methods. In order to overcome the intrinsic limitations of classical molecular dynamics, this Ph.D. project focuses on the application of advanced sampling computational techniques to capture the plasticity of diverse biological systems. The first of these applications involved the evaluation of the secondary structure of the N-terminal portion of p53 and its inverse, reverse and retro-inverso sequences by using replica exchange molecular dynamics simulations in implicit solvent. In this study, we also evaluated the effects of reversal of sequence and stereochemistry in mimicking an inhibitory pharmacophoric conformation. The results showed how the ability to mimic the parent peptide is severely compromised by backbone orientation (for D-amino acids) and side-chain orientation (for reversed sequences). Moreover, the structural information obtained from simulations showed good agreement with NMR and circular dichroism studies, confirming the validity of the combination of replica exchange molecular dynamics with the ff99SB force field and Generalized Born solvent model for computational modelling of D-peptide conformations.In a second work, we explored conformations of the DFG motif of the p38α mitogen-activated protein (MAP) kinase. To achieve this, we employed an advanced sampling simulation method that has been developed in-house, called swarm-enhanced sampling molecular dynamics (sesMD). In contrast to multiple independent MD simulations, swarm-coupled sesMD trajectories were able to sample a wide range of DFG conformations, some of which map onto existing crystal structures. Simulated structures intermediate between DFG-in and DFG-out conformations were predicted to have druggable pockets of interest for structure-based ligand design. Overall, sesMD shows promise as a useful tool for enhanced sampling of complex conformational landscapes. Finally, we used microsecond MD simulations to evaluate the molecular plasticity of R-spondins, a class of proteins involved in the activation of the Wnt pathway. The unbound R-spondin 1 is characterised by a closed conformation, while, when complexed to proteins LGR and RNF43/ZNRF3, assumes an open and more extended arrangement. This is true also for R-spondin 2, in both its unbound or bound forms. From our simulation, we find that the closed R-spondin 1 conformation is stable, whilst, R-spondin 1 and 2 from their open conformation explore several intermediate structures. In addition, we evaluated the druggability of a potential binding site located at the interface between the second and the third β-hairpin moiety of the first furin domain. The computational screening with small molecular fragments provided interesting insights about the druggability and the pharmacophoric features of the potential binding pockets identified, outlining promising future perspectives of structure-based design of Wnt pathway inhibitors.
4
Zhang, Wei. "Computational simulation of biological systems studies on protein folding and protein structure prediction /." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file 2.84Mb, 184 p, 2005. http://wwwlib.umi.com/dissertations/fullcit/3181881.
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Hafner, Melanie Salome [Verfasser]. "Structural conformational analysis of molecular dynamics of a P-glycoprotein homology model and generated intermediate structures / Melanie Salome Hafner." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/119893316X/34.
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Tippel, Franziska [Verfasser], Johannes [Akademischer Betreuer] Buchner, Michael [Gutachter] Sattler, and Johannes [Gutachter] Buchner. "Mechanistic Analysis of Conformational Dynamics of the Molecular Chaperone Hsp90 / Franziska Tippel ; Gutachter: Michael Sattler, Johannes Buchner ; Betreuer: Johannes Buchner." München : Universitätsbibliothek der TU München, 2017. http://d-nb.info/1173898832/34.
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Tippel, Franziska Verfasser], Johannes [Akademischer Betreuer] [Buchner, Michael [Gutachter] Sattler, and Johannes [Gutachter] Buchner. "Mechanistic Analysis of Conformational Dynamics of the Molecular Chaperone Hsp90 / Franziska Tippel ; Gutachter: Michael Sattler, Johannes Buchner ; Betreuer: Johannes Buchner." München : Universitätsbibliothek der TU München, 2017. http://nbn-resolving.de/urn:nbn:de:bvb:91-diss-20170217-1341437-1-7.
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Alonso, Gil Santiago. "Conformational and mechanistic analyses of α- and β-glycosidase substrates by ab initio QM/MM methods". Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/462805.
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Carbohydrates are one of the most important biochemical molecules due to their role as energetic resource for non-photosynthetic organisms, cell-cell recognition and adhesion, protection of cell membranes of bacteria and plants and ensure the proper functionality of several enzymes. Glycoproteins are important components of cell surfaces and the extracellular medium where molecular-cell interactions take place. Defects in the activity of glycoproteins are the cause of several human diseases, such as diabetes and lysosomal storage diseases.
Glycoside hydrolases (GHs) are one of the most relevant glycoproteins. They catalyse the cleavage of glycosidic bonds of oligosaccharides to generate smaller oligosaccharides or monosaccharides with relevant biological roles. To know the proper way to modulate the activity of these enzymes, it is crucial to understand their molecular mechanisms of action. Sugars are very flexible molecules, most of them formed by 6- membered rings whose conformation changes during the reaction catalysed by GHs. Capturing these conformations, in particular the one at the reaction transition state, is important in inhibitor design. Experiments aimed at characterizing (indirectly) the transition state conformation of GHs include crystallizing the Michaelis complex (MC), which usually is done using thioglycoside derivatives of the natural substrate (i.e. the glycosidic oxygen is substituted by sulfur) or enzyme mutants (e.g. the catalytic acid/base residue mutated to glutamine or asparagine). However, in some cases, the degree of resemblance of the sugar conformation in thioglycosides or enzyme mutants with respect to the natural/wild type counterparts unclear.
In last years, our group has demonstrated that the conformational free energy landscape (FEL) of natural sugars (e.g. β-glucose, α,β-mannose and β-xylose) can be used to predict catalytic pathways of GHs. The conformational FEL is explored using Cremer & Pople puckering coordinates as collective variables in the metadynamics method. A natural extension of these studies is to explore the conformational FEL of 7-membered sugar rings (septanosides), which are currently the focus of great interest as potential GH substrates.
In this Thesis, we applied Car-Parrinello molecular dynamics methods, within the QM/MM approach, to elucidate the catalytic mechanism of a family 13 retaining GH, (amylosucrase) and a family 125 inverting GH (exo-1,6-α-mannosidase). In both cases, prior structural information was available from enzyme mutants and/or thioderivative substrates. In addition, we have extended previous ring conformational analyses of pyranoses to septanosides in order to assess their potential as new substrates of selected GHs.
The Thesis is organised as follows:
Chapters I and II focuses on the conformational flexibility of carbohydrates, GH mechanisms and experimental techniques aimed to trap the MC, as well as the methodology used in this Thesis.
In Chapter III, we investigate the conformational landscape of α-glucose and the conformational itinerary that an α-glucoside (fructose) follows during catalysis by GH13 amylosucrase (both hydrolysis and polymerization have been investigated).
In Chapter IV, we present the results of conformational study of a thioglycoside vs the natural substrate in a GH125 α-mannosidase, including a mechanistic analysis that uncovered the conformational catalytic itinerary for family 125 GHs.
In Chapter V, we investigate four MC structures of a promiscuous GH3 β- glucohydrolase, able to cleave several types of glycosidic linkages, for which only structures with thioglycosides are available. The reconstruction of the structure with the natural substrate allowed us to predict the mechanism of action of these enzymes.
In Chapter VI, we apply the Cremer & Pople puckering coordinates for 7-membered rings as collective variable for metadynamics on several septanoside molecules (both isolated and “on-enzyme”) and assess their potential as substrate/inhibitors of GHs.
Finally, Chapter VII contains the main conclusions of this work.<br>Los carbohidratos son una de las biomoléculas más importantes debido a su papel como fuente de energía para organismos no-fotosintéticos, reconocimiento célula-célula, protección de la membrana celular de bacterias y plantas y por asegurar la buena funcionalidad de algunas enzimas. Las glicoproteínas son componentes esenciales en la superficie de las células y en el medio extracelular. Defectos en la actividad de estas proteínas son la causa de varias enfermedades humanas, como la diabetes o problemas en el lisosoma.
Las glicosil hidrolasas (GHs) son una de las glicoproteínas más relevantes. Catalizan la rotura de enlaces glicosídicos de oligosacáridos para generar monosacáridos o cadenas más pequeñas de azúcares con relevancia biológica. Para encontrar una manera adecuada de modular la actividad de estas enzimas, es crucial entender sus mecanismos moleculares. Los azúcares son moléculas muy flexibles, la mayoría formados por anillos de 6 átomos cuya conformación cambia durante la reacción en GHs. Capturar estas conformaciones, en particular la del estado de transición, es clave para diseñar inhibidores. La manera de caracterizar indirectamente la conformación de ese estado de transición es cristalizando el complejo de Michaelis de la GH con un tioderivado del sustrato natural (el oxígeno glicosídico es substituido por azufre) o usando mutantes de la enzima. No obstante, en algunos casos, la semejanza a nivel conformacional del mímico y el sustrato natural no queda suficientemente clara.
En los últimos años, nuestro grupo ha demostrado el uso para predecir itinerarios catalíticos de GHs a partir de las superficies de energía libre conformacional de los azúcares naturales (glucosa, manosa y xilosa). Estas superficies se exploran utilizando las coordenadas de empaquetamiento de Cremer y Pople como variables colectivas en el método de metadinámica. Una extensión de estos estudios es el análisis conformacional de azúcares formados por anillos de 7 átomos (septanósidos), que están actualmente en el foco de interés como sustratos de GHs.
En la presente Tesis, aplicamos métodos basados en dinámica molecular Car- Parrinello, dentro de la aproximación QM/MM, para estudiar el mecanismo catalítico de las GHs de la familia 13 (amilosucrasa), la familia 125 (exo-1,6-α-manosidasa) y la familia 3 (enzima HvExoI). Además, hemos extendido el estudio conformacional de
anillos a los septanósidos para poder predecir su potencial como nuevos sustratos de GHs concretas.
9
Posgai, Monica Therese. "Energetic and dynamic characterization of the IgA1:FcαRI interaction reveals long-range conformational changes in IgA1 upon receptor binding". University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1354043317.
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Bougueroua, Sana. "Caractérisation de structures explorées dans les simulations de dynamique moléculaire." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLV099/document.
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L’objectif de cette thèse est d’analyser et prédire les conformations d’un système moléculaire en combinant la théorie des graphes et la chimie computationnelle.Dans le cadre des simulations de dynamique moléculaire, une molécule peut avoir une ou plusieurs conformations au cours du temps. Dans les trajectoires de simulation de dynamique moléculaire, on peut avoir des trajectoires n’explorant qu’une seule conformation ou des trajectoires explorant plusieurs conformations, donc plusieurs transitions entre conformations sont observées. L’exploration de ces conformations dépend du temps de la simulation et de l'énergie (température) fixée dans le système. Pour avoir une bonne exploration des conformations d’un système moléculaire, il faut générer et analyser plusieurs trajectoires à différentes énergies. Notre objectif est de proposer un algorithme universel qui permet d’analyser la dynamique conformationnelle de ces trajectoires d’une façon rapide et automatique. Les trajectoires fournissent les positions cartésiennes des atomes du système moléculaire à des intervalles de temps réguliers. Chaque intervalle contenant un ensemble de positions est appelé image. L’algorithme utilise des règles de géométrie (distances, angles, etc.) sur les positions pour trouver les liaisons (liaisons covalentes, liaisons hydrogène et interactions électrostatiques) créées entre les atomes, permettant par la suite d’obtenir le graphe mixte qui modélise une conformation. Nous ne considérons un changement conformationnel que s’il y a un changement dans les liaisons calculées à partir des positions données. L’algorithme permet de donner l’ensemble des conformations explorées sur une ou plusieurs trajectoires, la durée d’exploration de chaque conformation, ainsi que le graphe de transitions qui contient tous les changements conformationnels observés.Les conformations se caractérisent par une énergie appelée énergie potentielle. Cette énergie est représentée par une courbe appelée surface d’énergie potentielle. En chimie théorique et computationnelle, certains s’intéressent à trouver des points particuliers sur cette surface. Il s'agit des minima qui représentent les conformations les plus stables et des maxima ou états de transition qui représentent les points de passage d'une conformation à une autre. En effet, d'une part, la conformation la plus stable est celle de plus basse énergie. D'autres part, pour aller d’une conformation à une autre il faut une énergie supplémentaire, le point maximum représente l'état de transition. Les méthodes développées pour calculer ces points nécessitent une connaissance de l’énergie potentielle ce qui est coûteux en temps et en calculs. Notre objectif est de proposer une méthode alternative en utilisant des mesures ah doc basées sur des propriétés des graphes qu’on a utilisées dans le premier algorithme et sans faire appel à la géométrie ni aux calculs moléculaires. Ces mesures permettent de générer des conformations avec un classement énergétique ainsi de définir le coût énergétique de chaque transition permise. Les conformations possibles avec les transitions représentent respectivement les sommets et les arcs de ce qu’on appelle le “graphe des possibles”. Les hypothèses utilisées dans le modèle proposé est que seules les liaisons hydrogène peuvent changer entre les conformations et que le nombre de liaisons hydrogène présentes dans le système permet de déterminer son coût énergétique.L’algorithme d'analyser des trajectoires a été testé sur trois types de systèmes moléculaires en phase gazeuse de taille et de complexité croissantes. Bien que la complexité théorique de l’algorithme est exponentielle (tests d’isomorphisme) les résultats ont montré que l’algorithme est rapide (quelques secondes). De plus, cet algorithme peut être facilement adapté et appliqué à d’autres systèmes. Pour la prédiction conformationnelle, le modèle proposé a été testé sur des peptides isolés<br>This PhD is part of transdisciplinary works, combining graph theory and computational chemistry.In molecular dynamics simulations, a molecular system can adopt different conformations over time. Along a trajectory, one conformation or more can thus be explored. This depends on the simulation time and energy within the system. To get a good exploration of the molecular conformations, one must generate and analyse several trajectories (this can amount to thousands of trajectories). Our objective is to propose an automatic method that provides rapid and efficient analysis of the conformational dynamics explored over these trajectories. The trajectories of interest here are in cartesian coordinates of the atoms that constitute the molecular system, recorded at regular time intervals (time-steps). Each interval containing a set of positions is called a snapshot. At each snapshot, our developed algorithm uses geometric rules (distances, angles, etc.) to compute bonds (covalent bonds, hydrogen bonds and any other kind of intermolecular criterium) formed between atoms in order to get the mixed graph modelling one given conformation. Within our current definitions, a conformational change is characterized by either a change in the hydrogen bonds or in the covalent bonds. One choice or the other depends on the underlying physics and chemistry of interest. The proposed algorithm provides all conformations explored along one or several trajectories, the period of time for the existence of each one of these conformations, and also provides the graph of transitions that shows all conformational changes that have been observed during the trajectories. A user-friendly interface has been developed, that can de distributed freely.Our proposed algorithm for analysing the trajectories of molecular dynamics simulations has been tested on three kinds of gas phase molecular systems (peptides, ionic clusters). This model can be easily adapted and applied to any other molecular systems as well as to condensed matter systems, with little effort. Although the theoretical complexity of the algorithm is exponential (isomorphism tests), results have shown that the algorithm is rapid.We have also worked on computationally low cost graph methods that can be applied in order to pre-characterize specific conformations/points on a potential energy surface (it describes the energy of a system in terms of positions of the atoms). These points are the minima on the surface, representing the most stable conformations of a molecular system, and the maxima on that surface, representing transition states between two conformers. Our developed methods and algorithms aim at getting these specific points, without the prerequisite knowledge/calculation of the potential energy surface by quantum chemistry methods (or even by classical representations). By avoiding an explicit calculation of the potential energy surface by quantum chemistry methods, one saves computational time and effort. We have proposed an alternative method using ad doc measures based on properties of the graphs (already used in the first part of the PhD), without any knowledge of energy and/or molecular calculations. These measures allow getting the possible conformations with a realistic energy classification, as well as transition states, at very low computational cost. The algorithm has been tested on gas phase peptides
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Pham, Khoa Ngoc. "Conformational Dynamics and Stability Associated with Magnesium or Calcium Binding to DREAM in the Regulation of Interactions between DREAM and DNA or Presenilins." FIU Digital Commons, 2016. http://digitalcommons.fiu.edu/etd/2589.
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Downstream regulatory element antagonist modulator (DREAM) is involved in various interactions with targets both inside and outside of the nucleus. In the cytoplasm, DREAM interacts with the C-terminal fragments of presenilins to facilitate the production of β-amyloid plaques in Alzheimer’s disease. In the nucleus, Ca2+ free DREAM directly binds to specific downstream regulatory elements of prodynorphin/c-fos gene to repress the gene transcription in pain modulation. These interactions are regulated by Ca2+ and/or Mg2+ association at the EF-hands in DREAM. Therefore, understanding the conformational dynamics and stability associated with Ca2+ and/or Mg2+ binding to DREAM is crucial for elucidating the mechanisms of interactions of DREAM with DNA or presenilins. The critical barrier for envisioning the mechanisms of these interactions lies in the lack of NMR/crystal structures of Apo and Mg2+DREAM.
Using a combination of fluorescence spectroscopy, circular dichroism, isothermal titration calorimetry, photothermal spectroscopy, and computational approaches, I showed that Mg2+ association at the EF-hand 2 structurally stabilizes the N-terminal alpha-helices 1, 2, and 5, facilitating the interaction with DNA. Binding of Ca2+ at the EF-hand 3 induces significant structural changes in DREAM, mediated by several hydrophobic residues in both the N- and C-domains. These findings illustrate the critical role of EF-hand 3 for Ca2+ signal transduction from the C- to N-terminus in DREAM. The Ca2+ association at the EF-hand 4 stabilizes the C-terminus by forming a cluster consisting of several hydrophobic residues in C-terminal domain. I also demonstrated that association of presenilin-1 carboxyl peptide with DREAM is Ca2+ dependent and the complex is stabilized by aromatic residues F462 and F465 from presenilin-1 and F252 from DREAM. Stabilization is also provided by residues R200 and R207 in the loop connecting a7 and a8 in DREAM and the residues D450 and D458 in presenilin-1.
These findings provide a structural basis for the development of new drugs for chronic pain and Alzheimer’s disease treatments.
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Sit, Kei Chun. "Investigation of the binding interactions between insulin and its receptor." Thesis, Queensland University of Technology, 2015. https://eprints.qut.edu.au/87276/1/Kei_Sit_Thesis.pdf.
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This project investigated the interactions between insulin and its receptor. A combination of computational and experimental investigations resulted in the identification of four residues in non-canonical sites that, when mutated, had detrimental effects on insulin binding. An increased understanding of the binding mechanism will aid future research into diseases involving the insulin receptor and its relatives and could potentially lead to new therapeutic avenues to combat these health related issues.
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Jaime, Rodríguez Juan Carlos. "Unveiling Heparin and Heparan Sulfate Conformations : a Journey into Paramagnetic NMR Analysis." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASF016.
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L'héparine (HP) et les héparane sulfates (HS) sont des polysaccharides sulfatés linéaires qui jouent divers rôles biologiques, notamment dans la croissance cellulaire, l'adhésion, la reconnaissance virale et la métastase du cancer. Leur variété moléculaire et leur motif de sulfatation contribuent à leur polyvalence biologique. Par ailleurs, leur flexibilité conformationnelle a été étudiée par des méthodes telles que la cristallographie aux rayons X et la RMN. Malgré des avancées, interpréter ces caractéristiques reste difficile, surtout pour de longs saccharides. Cette thèse propose l'utilisation de la RMN paramagnétique, notamment des déplacements de pseudo-contacts (PCS), dans l’étude conformationnelle des molécules d’HS. Les résultats obtenus sur un octasaccharide d'HS, montrent une corrélation entre les PCS expérimentales et les simulations de dynamique moléculaire, suggérant des conformations spécifiques des motifs IdoA. Ces découvertes élargissent les applications de la RMN paramagnétique, ouvrant la voie à une analyse approfondie des interactions protéine-polysaccharide<br>Heparin (HP) and heparan sulfates (HS) are linear and sulfated polysaccharides that play various biological roles, including cell growth, adhesion, viral recognition, and cancer metastasis. Their molecular diversity and sulfation pattern contribute to their biological versatility. Furthermore, their conformational flexibility has been studied through methods such as X-ray crystallography and NMR. Despite advancements, interpreting these features remains challenging, especially for long saccharides. This thesis proposes the use of paramagnetic NMR, particularly pseudo-contact shifts (PCS) measurements, in studying the conformation of HS molecules. Results obtained on an HS octasaccharide show a correlation between experimental PCS and molecular dynamics simulations, suggesting specific conformations of IdoA motifs. These findings expand the applications of paramagnetic NMR, paving the way for a thorough analysis of protein-polysaccharide interactions
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Benabderrahmane, Mohammed. "Etude de la structure et la dynamique de Mcl-1 : application en cancérologie Binding mode of Pyridoclax to myeloid cell leukemia-1 (Mcl-1) revealed by nuclear magnetic resonance spectroscopy, docking and molecular dynamics approaches Insights into Mcl-1 Conformational States and Allosteric Inhibition Mechanism from Molecular Dynamics Simulations, Enhanced Sampling, and Pocket Crosstalk Analysis." Thesis, Normandie, 2020. http://www.theses.fr/2020NORMC426.
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Ce travail ayant pour objet l’étude de la structure et la dynamique de Mcl-1, une protéine anti-apoptotique d’intérêt en cancérologie, est scindé en trois parties.Une première étude concerne une caractérisation du mode d’interaction du Pyridoclax (un inhibiteur BH3-mimétique) avec Mcl-1 par des approches expérimentales (RMN) et théoriques (simulations de dynamique moléculaire). Une deuxième partie est consacrée à l’étude et à la caractérisation des espaces conformationnels de Mcl-1 et son mode d’inhibition allostérique. Le troisième volet de ce travail, traite d’une approche d’analyse, basée sur des simulations de métadynamique avec comme application la détection du répertoire des poches cryptiques de Mcl-1<br>This work, which aims to study the structure and dynamics of Mcl-1, an anti-apoptotic protein of interest in cancer, was carried out in three parts.A first study focused on a characterization of the interaction mode of Pyridoclax (a BH3-mimetic) with Mcl-1 by experimental (NMR) and theoretical approaches (molecular dynamics simulations). A second part is devoted to the study and characterization of the conformational space of Mcl-1 and its mode of allosteric inhibition. In the last part of this work, Metadynamics simulations on essential dynamics space as a general approach for Mcl-1’s cryptic pockets detection were evaluated
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Oliveira, Maria Weruska Pereira de. "Estudos conformacionais em compostos contendo íons lantanídeos." Universidade Federal da Paraíba, 2008. http://tede.biblioteca.ufpb.br:8080/handle/tede/7061.
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Previous issue date: 2008-11-13<br>Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES<br>Lanthanide macrocyclic complexes, especially containing Gd(III)
ions, are largely used as contrast agents in the medical diagnostic
technique named Magnetic Resonance Imaging (MRI). Theoretical
investigation of these compounds by molecular modeling methods is an
emerging research area today.
In this work we have performed a conformational study of the
following supramolecular compounds: the macrocyclic ligands 1,4,7,10-
tetraazacyclododecane (DOTA) and 1,4,7,10-tetraazacyclododecane-
1,4,7,10-tetraacetic acid (H4DOTA) and the macrocyclic complexes
[Gd(DOTA).H2O]- and Gd(PhenHDO3A).H2O, where PhenHDO3A is (rel-10-
[(5R,6R)-5,6-dihydro-6-hydroxy-1,10-Phenanthroline-5-yl)-1,4,7,10-
tetraazacyclododecane-1,4,7-triacetic acid).
For this, we have developed and carried out a procedure that
involves: (1) the sampling of the conformation space of these compounds
through some short molecular dynamics at different temperatures and (2)
full geometry optimization in the geometries obtained in the previous
stage using semi-empirical AM1 method for the macrocyclic ligands and
Sparkle/AM1 model for the macrocyclic lanthanide complexes.
Our results revealed that the high flexibility of non-coordinated
macrocyclic ligands DOTA and H4DOTA, helped us to test the ability of our
methodology to sample different regions of conformation space of these
compounds.
For the [Gd(DOTA).H2O]- complex, we were capable to find the
same conformational isomers which were reported in published works as
well as to comprehend relevant details about the mobility of the
coordinated water molecule. Furthermore, we also were capable to
identify some intermediate local minima related to the dynamics of
rotation of the coordinated acetate groups in the studied complexes as
well as to the dynamics of ring inversion of the coordinated
tetraazadodecane moiety in the Gd(PhenHDO3A).H2O.
In conclusion, we possess now an interesting strategy to conduct the
search for conformational isomers of these compounds. This knowledge is
very important to be applied in the rational design of new molecules to act
as contrast agent in MRI.<br>Complexos macrocíclicos de lantanídeos, em especial com o íon
Gd(III), são cada vez mais utilizados como agentes de contrastes na
técnica médica de diagnóstico, imagem por ressonância magnética nuclear
(MRI). O estudo teórico de novos agentes de contrastes através de
modelagem molecular é uma área de pesquisa em grande expansão.
No nosso trabalho fizemos um estudo conformacional dos seguintes
compostos supramoleculares: os ligantes macrocíclicos 1,4,7,10-
tetraazaciclododecano (DOTA) e ácido 1,4,7,10-tetraazaciclododecano-
1,4,7,10-tetraacético (H4DOTA), o complexo macrocíclico
[Gd(DOTA)H2O]- e o complexo macrocíclico Gd(PhenHDO3A).H2O, onde
PhenHDO3A é (rel-10-[(5R,6R)-5,6-dihidro-6-hidroxi-1,10-fenantrolina-5-
il)-1,4,7,10-tetraazaciclododecano-1,4,7-ácido triacético).
Para isso, elaboramos e executamos um procedimento que envolve
o mapeamento ou amostragem do espaço conformacional desses
compostos através de dinâmicas moleculares curtas em diferentes
temperaturas para em seguida, essas geometrias serem usadas como
pontos de partida para otimização de geometria usando tanto o método
semi-empírico AM1 quanto o modelo Sparkle/AM1.
Como resultado, podemos citar que a elevada flexibilidade dos
ligantes macrocíclicos não coordenados DOTA e H4DOTA, serviu para
testar a capacidade da nossa metodologia de visitar regiões distintas do
espaço conformacional.
Para o complexo [Gd(DOTA)H2O]-, conseguimos encontrar os
mesmos isômeros conformacionais que já são reportados em outros
estudos, bem como revelar detalhes relativos à mobilidade da molécula de
água coordenada. Além disso, conseguimos identificar mínimos locais
intermediários que estão relacionados com a dinâmica de rotação dos
grupos acetato em ambos os complexos e a dinâmica de inversão do anel
tetraazadodecano no complexo Gd(PhenHDO3A).H2O.
A relevância desse trabalho está apoiada no fato de que agora
temos uma estratégia interessante para realizar a busca de isômeros
conformacionais desses compostos, sendo essas informações, muito
importantes quando se deseja projetar uma nova molécula para atuar
como agente de contraste em MRI.
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Phillips, Jonathan James. "Conformational dynamics of the molecular chaperone HSP90." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612814.
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Bruce, Neil John. "Investigating protein conformational change via molecular dynamics simulation." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/investigating-protein-conformational-change-via-molecular-dynamics-simulation(17145939-f643-4b23-bbb9-029cf5489c15).html.
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Accumulation and aggregation of the 42-residue amyloid-[beta] (A[beta]) protein fragment, which originates from the cleavage of amyloid precursor protein by beta and gamma secretase, correlates with the pathology of Alzheimer's disease (AD). Possible therapies for AD include peptides based on the A[beta] sequence, and recently identified small molecular weight compounds designed to mimic these, that interfere with the aggregation of A[beta] and prevent its toxic effects on neuronal cells in culture. Here, we use molecular dynamics simulations to compare the mode of interaction of an active (LPFFD) and inactive (LHFFD) [beta]-sheet breaker peptide with an A[beta] fibril structure from solid state NMR studies. We found that LHFFD had a weaker interaction with the fibril than the active peptide, LPFFD, from geometric and energetic considerations, as estimated by the MM/PBSA approach. Cluster analysis and computational alanine scanning identified important ligand-fibril contacts, including a possible difference in the effect of histidine on ligand-fibril [pi]-stacking interactions, and the role of the proline residue establishing contacts that compete with those essential for maintenance of the inter-monomer [beta]-sheet structure of the fibril. Our results show that molecular dynamics simulations can be a useful way to classify the stability of docking sites. These mechanistic insights into the ability of LPFFD to reverse aggregation of toxic A[beta] will guide the redesign of lead compounds, and aid in developing realistic therapies for AD and other diseases of protein aggregation. We have also performed long explicit solvent MD simulations of unliganded amyloid fibril in three putative protonation states, in order to better understand the energetic and mechanical features of the fibril receptor. Over 100 ns MD simulations, the trajectories where fibril has Glu11 and Glu22 side-chains protonated exhibit the least deviation from the initial solid state NMR structures. Free energy calculations on these rajectories suggest that the weakest fibril interface lies in the lateral rather than transverse direction and that there is little dependence on whether the lateral interface is situated at the edge or middle of the fibril. This agrees with recent reported steered molecular dynamics calculations. Secondly, in an effort to improve the ability of atomistic simulation techniques to directly resolve protein tertiary structure from primary amino acid sequence, we explore the use of a molecular dynamics technique based on swarm intelligence, called SWARM-MD, to identify the native states of two peptides, polyalanine and AEK17, as well as Trp-cage miniprotein. We find that the presence of cooperative swarm interactions significantly enhanced the efficiency of molecular dynamics simulations in predicting native conformation. However, it also is evident that the presence of outlying simulation replicas can adversely impact correctly folded replica structures. By slowly removing the swarm potential after folding simulations, the negative effect of the swarm potential can be alleviated and better agreement with experiment obtained.
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Barton, Nicholas Paul. "Investigating the conformational flexibility of calmodulin." Thesis, University of York, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274501.
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Bossa, Cecilia. "Conformational fluctuations in proteins. A molecular dynamics based study." Doctoral thesis, La Sapienza, 2005. http://hdl.handle.net/11573/916821.
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Ma, Ning. "On the Conformational Dynamics of DNA: A Perspective from Molecular Dynamics Simulations." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6729.
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The main focus of my dissertation is on the conformational motion of DNA, studied by applying tools from the computational chemistry field. In addition, studies of relative α- and 310 helical stabilities in peptides/mini-proteins, and a molecular flooding study of the retinoid X-receptor as part of a continuing drug design effort are presented. In molecular biology, it has been well known that sequence determines structure, and structure controls function. For proteins or DNA to work properly, the correct configuration is required. Mutations may alter the structure, which can cause malfunction. Non-mutational effects, such as a change in environment may also cause a configurational change and in turn change the functionality of the protein or DNA. Many experimental technics have been developed to investigate the structural or configurational aspects of biological systems, and molecular dynamics simulation has been proven to be a useful complementary tool to gain insights into this problem due to its ability to explore the dynamics and energetics of biomolecular processes at high spatial and time resolution. Molecular dynamics simulations are constrained by the available computational power, but several computational techniques have been developed to reduce computational costs. Also, development of hardware has helped the issue.
Years of hard work on force field parameter optimization built a solid foundation for molecular dynamics simulations, so that the computational model can satisfactory describe many biochemical systems in detail. Techniques such as umbrella ix sampling and reweighting methods have allowed researchers to construct free energy landscapes to reveal the relative stabilities of each major configurational state and the free energy barriers between configurations from relatively short simulations, a process which would otherwise require many microseconds of unbiased simulations.
My dissertation applies multiple advanced simulation techniques to investigate several DNA conformational problems, including the coupling between DNA bending and base flipping, the anisotropy of DNA bending, and intercalation of the dye in a Cy3 labeled DNA system. The main part of this work addressed a long standing question about DNA bending: does DNA prefer to bend toward the major or minor groove. My simulations not only answered this question, but also identified the mechanism by which the one direction is favored. Another part describes peptide/mini-protein helical transitions and studies benefiting ligand design for the retinoid X-receptor.
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Krukenberg, Kristin A. "Solution structures and conformational dynamics of the molecular chaperone Hsp90." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. 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:3359554.
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Willis, Peter G. "DESIGNING MOLECULAR RECOGNITION IN THE CONTEXT OF HYDROGEN BONDING AND MOLECULAR DYNAMICS." UKnowledge, 2001. http://uknowledge.uky.edu/gradschool_diss/279.
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The effect of hydrogen bonding on the conformation of organic moleculesunifies two projects in this thesis. In one project, the stability of the intramolecularhydrogen bond in derivatives of 2-guanidinobenzimidazole was studied bydynamic 1H NMR spectrometry. The impact that this intramolecular hydrogenbond had on the bond order of the neutral guanidino group and on the dynamicconformation of these aromatic structures was related to the concept of hydrogenbond-assisted resonance. In another project, an oligomer possessing repetitiveconformation and capable of much inter- and intramolecular hydrogen bondingwas designed and synthesized. The sensitivity of this oligomer to changes inanion concentration, as well as its own propensity to self-aggregate weremeasured.Hydrogen bonds found in many biological oligomers are connected thougha system of conjugated bonds. Guanidinobenzimidazole is a conjugated systemof carbon and nitrogen, connected by an intramolecular hydrogen bond. Severalderivatives of guanidinobenzimidazole were synthesized, and the effect ofseveral simple alkyl for hydrogen substitutions were studied.Guanidinobenzimidazole was used as a model to study what effect theconjugation and the intramolecular hydrogen bond have on each other.The formation of redundant low energy hydrogen bonds is universal inbiological oligomers. In DNA and RNA multiple hydrogen bonds are formed witha typical energy contribution of only 1-2 kcal/mol. Individually, these interactionsdo not give the biological oligomers their conformational stability, but togetherthey are very stable. The urea and amide based oligomers designed in the workand discussed in the thesis should form multiple hydrogen bonds withthemselves and/or with anionic guests. Chiral oligoureas were designed topossess this characteristic of cooperative conformation that so many biologicaloligomers and polymers share.
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Chatterjee, P. "Protein thermal stability, conformational dynamics and solvent properties: insights with atomistic molecular dynamics simulations." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2015. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/2242.
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Östervall, Jennie. "Conformational Dynamics of Carbohydrates Studied by NMR Spectroscopy and Molecular Simulations." Doctoral thesis, Stockholms universitet, Institutionen för organisk kemi, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-1023.
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Carbohydrates play important roles in biological processes. Their function is closely related to their conformation. In this thesis, conformational studies of carbohydrates by NMR spectroscopy and molecular dynamics computer simulations are described. The first two papers discuss the anomalous solubility of β-cyclodextrin compared to other cyclodextrins. Time correlation functions revealed flexibility in all cyclodextrins. Molecular dynamics computer simulations showed that the glycosidic linkages were rather rigid and the flexibility was suggested to be macrocyclic. From spatial distribution functions β-cyclodextrin was found to have greater ability to order the surrounding water than the other cyclodextrins. Paper III deals with some of the difficulties of conformational studies. In Paper IV, a new method, Additative Potential Maximum Entropy, APME, is applied to a disaccharide. Conformational distribution functions are derived from NOEs, J-couplings and residual dipolar couplings and calculated from computer simulations. All distribution functions were found to be in good agreement. In papers V and VI oligosaccharides from human milk are studied. Residual dipolar coupling, J-couplings and cross relaxation rates were measured by NMR spectroscopy and molecular dynamics computer simulations were carried out. Both oligosaccharides showed high flexibility for the β-D-GlcpNAc-(1→3)-β-D-Galp linkage.
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Östervall, Jennie. "Conformational dynamics of carbohydrates studied by NMR spectroscopy and molecular simulations /." Stockholm : Department of Organic Chemistry, Stockholm University, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-1023.
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Gray, Geoffrey M. "Conformational Fluctuations of Biomolecules Studied Using Molecular Dynamics and Enhanced Sampling." Scholar Commons, 2018. http://scholarcommons.usf.edu/etd/7156.
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Biomolecule structural fluctuations determine function, regulating numerous biological processes My research has shed light on several interesting cases in which structural fluctuations have been identified to assess functional differences. Chapter 2 discusses the effects of structural rearrangement of the β2-β3 loop on the DNA binding affinity of the type 6 human papillomavirus E2 protein. Chapter 3 investigates the effects of phosphorylation on the C-terminal domain of Cdc37, a protein important in the Hsp90 chaperone cycle. Chapter 4 studies the effects on cyclycization on the conformational fluctuations of a γ-AApeptide used for high-throughput libraries. Chapter 5 is a structural study on a mini-fibril of spider dragline silk, in which a native-like ensemble was generated using temperature replica exchange. Chapter 6 investigates the structural features of repetitive motifs found in spider dragline silk when subject to both dope-like and fiber-like conditions. Chapter 7 elucidates conformational differences between the RXRα and the RXRβ ligand-binding domains and seeks to understand the atomic basis for different ligand binding affinities. This body of work has contributed to the understanding of conformational fluctuations and changes that occur in protein-DNA binding systems, drug-binding, regulation of chaperones via post-translations modifications and spider dragline silk.
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Collins, Nathanael. "Conformational analysis and molecular modelling of cyclic hexapeptides." Thesis, University of Southampton, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357259.
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Grail, Barry Mark. "Molecular recognition of peptides." Thesis, Bangor University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248898.
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D'Rozario, Robert S. G. "Conformational dynamics of proline-containing transmembrane helices." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670181.
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Di, Palma Francesco. "Conformational changes in the adenine riboswitch." Doctoral thesis, SISSA, 2014. http://hdl.handle.net/20.500.11767/3889.
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Riboswitches are cis-acting genetic control elements that have been found in the un- traslated region of some mRNAs in bacteria and plants. Riboswitches are known to regulate the genetic expression by means of conformational changes triggered by highly specific interactions of the aptamer with the sensed metabolite. The non-coding sequence in the mRNA of add gene from V. vulnificus contains an adenine responsive riboswitch. Classical molecular dynamics simulations of its aptamer have been performed, both in presence and absence of its physiological ligand starting from the experimental crystal structure. We first use steered MD to induce the opening of the P1 stem and investigate its stability. Our results show that the ligand directly stabilizes the P1 stem by means of stacking interactions quantitatively consistent with thermodynamic data. Then, using both umbrella sampling and a combination of metadynamics and hamiltonian replica exchange, we show that the formation of L2-L3 kissing complex cooperates with ligand binding and we quantify the ligand-induced stabilization. In this context also the influ- ence given by either the monovalent cations or divalent cations was evaluated. Confor- mational changes at pairings detailed level are characterized using a recently introduced technique that is able to distinguish and classify each interaction (i.e. Watson-Crick base pair, non-canonical bp, stacking). Results are compatible with known experimental measurements and shed a new light on the ligand-dependent folding mechanism of the adenine riboswitch.
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Ahlstrom, Logan Sommers. "Molecular Dynamics Simulation of the Effect of the Crystal Environment on Protein Conformational Dynamics and Functional Motions." Diss., The University of Arizona, 2012. http://hdl.handle.net/10150/255200.
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Proteins are dynamic and interconvert between different conformations to perform their biological functions. Simulation methodology drawing upon principles from classical mechanics - molecular dynamics (MD) simulation - can be used to simulate protein dynamics and reconstruct the conformational ensemble at a level of atomic detail that is inaccessible to experiment. We use the dynamic insight achieved through simulation to enhance our understanding of protein structures solved by X-ray crystallography. Protein X-ray structures provide the most important information for structural biology, yet they depict just a single snapshot of the solution ensemble, which is under the influence of the confined crystal medium. Thus, we ask a fundamental question - how well do static X-ray structures represent the dynamic solution state of a protein? To understand how the crystal environment affects both global and local protein conformational dynamics, we consider two model systems. We first examine the variation in global conformation observed in several solved X-ray structures of the λ Cro dimer by reconstructing the solution ensemble using the replica exchange enhanced sampling method, and show that one X-ray conformation is unstable in solution. Subsequent simulation of Cro in the crystal environment quantitatively assesses the strength of packing interfaces and reveals that mutation in the lattice affects the stability of crystal forms. We also evaluate the Cro models solved by nuclear magnetic resonance spectroscopy and demonstrate that they represent unstable solution states. In addition to our studies of the Cro dimer, we investigate the effect of crystal packing on side-chain conformational dynamics through solution and crystal MD simulation of the HIV microbicide Cyanovirin-N. We find that long, polar surface side-chains can undergo a strong reduction in conformational entropy upon incorporation into crystal contacts, which supports the application of surface engineering to facilitate protein crystallization. Finally, we outline a general framework for using network visualization to aid in the functional interpretation of conformational ensembles generated from MD simulation. Our results will enhance the understanding of X-ray data in establishing protein structure-function-dynamics relationships.
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Simsir, Méliné. "Modélisation structurale des pompes à efflux de la famille des RND : de la résistance aux antibiotiques à la résistance à la chimiothérapie." Electronic Thesis or Diss., Université Côte d'Azur, 2020. http://www.theses.fr/2020COAZ6040.
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La résistance à la chimiothérapie peut-être étudiée comparativement à l’étude de la résistance chez les microorganismes. Parmi les superfamilles de protéine identifiées comme étant responsables de résistance aux drogues, il y a les RND. Ses membres sont très répandus dans les organismes bactériens, mais aussi les archaea et les eucaryotes. Ptch1, protéine transmembranaire récepteur du morphogène Hedgehog (Hh), membre des RND, a une activité d’efflux de cholestérol, mais aussi de médicaments chimiothérapeutiques qui confère aux cellules cancéreuses une résistance à la chimiothérapie. Or, une activité aberrante de la voie de signalisation Hh a été observée dans près de 25 % des cancers. Parmi les caractéristiques communes à la résistance aux drogues des RND, il y a la capacité de ces protéines transmembranaires à faire de l’efflux d’un large spectre de substrats et de drogues, et ce, en utilisant la force proton motrice.L’objectif de ce projet est l’étude structurale du mécanisme d’efflux de drogues de Ptch1.Dans un premier temps, n’ayant pas encore accès à une structure de Ptch1, nous avons réalisé une analyse des nombreuses structures disponibles de son homologue bactérien AcrB, modèle paradigme des RND responsable de résistance aux antibiotiques chez les bactéries gram négatives, afin de mieux comprendre le mécanisme d’efflux de drogues de ces protéines. Nous avons mis en place une stratégie d’analyse conformationnelle de l’ensemble des structures disponibles de façon à expliquer le mécanisme complexe, notamment ceux d’efflux de drogues de ces protéines, en fonction des propriétés structurales et dynamiques de sous-domaines. Les outils développés ont été mis à disposition de la communauté.Les structures de Ptch1 publiées en 2018 et 2019 ont révélé que le mécanisme d’efflux de drogues de Ptch1 était probablement très différent de celui d’AcrB. Dans un second temps, en utilisant ces structures, nous avons étudié le mécanisme d’efflux de cholestérol de Ptch1 par dynamique moléculaire afin d’étudier par la suite celui des drogues. Nous avons ainsi identifié certaines caractéristiques des changements conformationnels pouvant avoir lieu afin de permettre cet efflux. Enfin, le docking des agents chimiothérapeutiques transportés par Ptch1 suggère que les drogues utilisent les mêmes sites d’interaction que le cholestérol et potentiellement le même mécanisme d’efflux<br>Resistance to chemotherapy can be studied comparatively to the study of resistance in microorganisms. Among the protein superfamily identified as being responsible for multidrug resistance are RND. Its members are widespread in bacterial organisms, but also in Archaea and Eukaryotes. Ptch1, a transmembrane protein, receptor of morphogen Hedgehog (Hh), a member of the RND, has cholesterol efflux activity, but also of chemotherapeutic drugs which confers resistanceto chemotherapy to cancer cells. In fact, an aberrant activity of the Hh signaling pathway has been observed in nearly 25% of cancers. Among the common features of multidrug resistance in RND is the ability of these transmembrane proteins to efflux a broad spectrum of substrates and drugs using protonmotive force.The goal of this project is the structural study of the drug efflux mechanism of Ptch1.In a first step, since we did not yet have access to a structure of Ptch1, we have performed an analysis of the numerous available structures of its bacterial counterpart AcrB, the RND paradigm model responsible for antibiotic resistance in gram-negative bacteria, in order to better understand the drug efflux mechanism of these proteins. We have implemented a strategy of conformational analysis of all available structures in order to explain the complex mechanism, including the drug efflux mechanism of these proteins, as a function of the structural and dynamic properties of sub-domains. The tools developed have been made available to the community.The structures of Ptch1 published in 2018 and 2019 revealed that the drug efflux mechanism of Ptch1 was probably very different from that of AcrB. In a second step, using these structures, we studied the cholesterol efflux mechanism of Ptch1 by molecular dynamics in order to subsequently study the drug efflux mechanism. We thus identified certain characteristics of the conformational changes that cantake place to allow this efflux. Finally, the docking of chemotherapeutic agents carried by Ptch1 suggests that drugs use the same interaction sites as cholesterol and potentially the same efflux mechanism
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Zhou, Guangfeng. "STATISTICAL MODELS AND THEIR APPLICATIONS IN STUDYING BIOMOLECULAR CONFORMATIONAL DYNAMICS." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/478773.
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Chemistry<br>Ph.D.<br>It remains a major challenge in biophysics to understand the conformational dynamics of biomolecules. As powerful tools, molecular dynamics (MD) simulations have become increasingly important in studying the full atomic details of conformational dynamics of biomolecules. In addition, many statistical models have been developed to give insight into the big datasets from MD simulations. In this work, I first describe three statistical models used to analyze MD simulation data: Lifson-Roig Helix-Coil theory, Bayesian inference models, and Markov state models. Then I present the applications of each model in analyzing MD simulations and revealing insight into the conformational dynamics of biomolecules. These statistical models allow us to bridge microscopic and macroscopic mechanisms of biological processes and connect simulations with experiments.<br>Temple University--Theses
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Durst, Gregory L. "Conformational analysis of phosphine ligands, using molecular mechanics and cone angle calculations." Virtual Press, 1988. http://liblink.bsu.edu/uhtbin/catkey/539633.
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An empirical approach to the study of phosphine compounds was completed using Molecular Mechanics 2 (MM2), and several computer programs written to descibe and analyze the final geometric orientations of the molecules. The calculations were performed on 64 conformers of 16 different phosphines. Results from these calculations were compared to those previously obtained for MNDO and MINDO/3 calculations, and to experimental data. Cone angles calculated from the MM2 optimized geometries, were compared to Tolman's original work, and to values obtained from semiempirical calculations, and to experimental results. In general, it was found that weighted average cone angles best represent the size of phosphine ligands.<br>Department of Chemistry
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Karolak, Aleksandra. "Application and Development of Computational Methods in Conformational Studies of Bio-molecules." Scholar Commons, 2015. https://scholarcommons.usf.edu/etd/5520.
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The work presented in my dissertation focuses on the conformational studies of bio-molecules including proteins and DNA using computational approaches. Conformational changes are important in numerous molecular bioprocesses such as recognition, transcription, replication and repair, etc. Proteins recognize specific DNA sequences and upon binding undergo partial or complete folding or partial unfolding in order to find the optimal conformational fit between molecules involved in the complex. In addition to sequence specific recognition, proteins are able to distinguish between subtle differences in local geometry and flexibility associated with DNA that may further affect their binding affinities. Experimental techniques provide high-resolution details to the static structures but the structural dynamics are often not accessible with these methods; but can be probed using computational tools. Various well-established molecular dynamics methods are used in this work to study differences in geometry and mechanical properties of specific systems under unmodified and modified conditions. Briefly, the studies of several protein and DNA systems investigated the importance of local interactions and modifications for the stability, geometry and mechanical properties using standard and enhanced molecular dynamics simulations. In addition to the conformational studies, the development of a new method for enhanced sampling of DNA step parameters and its application to DNA systems is discussed.
Chapter 1 reviews the importance of the conformational changes in bioprocesses and the theory behind the computational methods used in this work. In the project presented in chapter 2 unbiased molecular dynamics and replica exchange molecular dynamics are employed to identify the specific local contacts within the inhibitory module of ETS-1. ETS-1 is a human transcription factor important for normal but also malignant cell growth. An increased concentration of this protein is related to a negative prognosis in many cancers. A part of the inhibitory module, inhibitory helix 1 (HI-1) is located on the site of the protein opposite to the DNA binding site and although loosely packed, stays folded in the apo state and unfolds upon ETS-1 binding to DNA. Our study investigated the character and importance of contacts between HI-1 and neighboring helices of the inhibitory module: HI-2 and H4. We also identified a mutant of HI-1, which possessed the higher helical propensity than the original construct. This study supported the experimental findings and enhanced the field by the identification of new potential target for experimental tests of the system, which plausibly inhibits binding to DNA.
In the studies discussed in chapters 3-5 the conformational dynamics of DNA under normal conditions and upon specific epigenetic modifications are presented. Since DNA conformation can be accurately described by six base pair step parameters: twist, tilt, roll, shift, slide and rise, these were extensively analyzed and the results elucidated insights into the properties of the systems. In order to enhance unbiased simulations and allow for easier crossing of the energy barriers, we developed and implemented a novel method to control DNA base pair step parameters. With this approach we obtained the free energy estimates of e.g. DNA rearrangements in a more efficient manner. This advanced computational method, supported by standard and additional enhanced techniques, was then applied in the studies of DNA methylation on cytosine or adenine bases and oxidative damage of cytosine.
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Jensen, C. H. "Molecular dynamics and complexity analysis of molecular systems." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.605591.
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In this thesis, Complexity Analysis, which is defined as the use of Markov models and Computational Mechanics, is applied to Molecular Dynamics simulations of peptides. To achieve this, the trajectories from the Molecular Dynamics simulations are clustered into conformational states and by investigating the time series of these states, statistical models are constructed. A basic property of a Markov model is that the probability distribution of the subsequent states depends only on the current state and not the history. This has previously been used to develop a method for testing the model which is based on calculating and comparing eigenvalues for Markov models constructed at different time steps. Here, the method is applied to a simulation of the four residue peptide VPAL and it is found that the Markov model is accurate at a minimum time step of 100ps. The determination of the time step using this test is, however, subjective, so I have developed a method which is based on Computational Mechanics to determine the minimum time step at which the dynamics are Markovian. An important part of the application of a Markov model is the clustering of the Molecular Dynamics simulation into conformational states. The effect of varying the clustering of the simulation is investigated by calculating the mean first passage times between conformational states as the cluster boundaries are varied. It is found that the mean first passage times are sensitive to specific clustering, and to reduce the model sensitivity to variations in clustering, it is especially important to exclude sparsely populated states from the model. Finally, it is demonstrated that the folding time of a slow folding protein can be very sensitive to changes in the Markov model transition matrix. This implies that folding times calculated using Molecular Dynamics cannot meaningfully be compared to folding times obtained from experiments.
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Tamura, Kouichi. "Atomistically Deciphering Functional Large Conformational Changes of Proteins with Molecular Simulations." 京都大学 (Kyoto University), 2016. http://hdl.handle.net/2433/215334.
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Menon, S. "Triggers for protein conformational changes and self-assembly probed with fully atomistic computer simulations." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2019. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/5845.
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Curuksu, Jeremy. "Conformational sampling by molecular mechanics and dynamics simulations applied to the flexibility of Nucleic acid." Paris 7, 2009. http://www.theses.fr/2009PA077013.
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Les thématiques adressées dans ma Thèse de Doctorat sont d'une part la flexibilité conformationelle des Acides Nucléiques étudiée par simulations en Dynamique Moléculaire. D'autre part, mes travaux de Thèse adressent deux problèmes principaux rencontrés lors de la pratique des simulations en dynamique moléculaire, à savoir l'échantillonnage limité et le champ de force spécifique utilisé. Trois issues scientifiques à propos de la flexibilité des molécules d'ADN et d'ARN font l'objet de trois chapitres distincts. Premièrement la possibilité d'une dynamique spontanée formant un coude flexible dans les motifs d'ARN ribosomales appelés kink-turns. Deuxièmement la formation spontanée d'un motif coudé très local dans les molécules d'ADN fortement courbées (« kink » entre deux paires de bases). Troisièmement un équilibre entre plusieurs sous états meta-stables dans les angles dièdres du squelette phosphodiester des molécules d'ADN endommagées, dans le cas présent un site abasique (base qui n'a pas de partenaire dans la double hélice d'ADN). Sur le niveau méthodologique nous avons implémenté une coordonnée de réaction spécifique pour chaque projet utilisant la méthode d'Echantillonnage Parapluie (Umbrella Sampling), et développé une nouvelle méthode d'échantillonnage dans le domaine des techniques dites en échange de réplicas (Replica Exchange). Finalement nous montrons qu'en combinant ces deux approches (donc « échantillonnage parapluie en échange de réplicas ») il en résulte un échantillonnage plus efficace et plus précis. Nos résultats permettent d'avoir une meilleure idée sur les coûts d'énergie libre impliqués dans le repliement et la courbure de divers motifs d'acide nucléique, en particulier les kinks dans l'ADN<br>My PhD dissertation deals with the application of atomic-scale computer simulation (Molecular Dynamics) on different aspects of the conformational flexibility of Nucleic Acids. I have used diverse statistical and computational methods such as Umbrella Sampling and Replica Exchange to extract entropic properties, e. G. Free energy, characterising (i) the bending of DNA on short length-scale, (ii) the folding of recently discovered RNA ribosomal motifs (the kink-tum motif) and (iii) backbone dihedral conformations accessible to damaged DNA. One achievement is the reproduction of the experimental curve for the probability of very high bend angles observed for short fragment of DMA which demonstrates a non linear (softer) bending flexibility of DMA. Indeed the results of my thesis predict that DMA kinks (local defects unstacking neighbour basepairs) occur in vivo and some of them induce a 90°-turn in the hélix. They are associated with a systematic decrease of the local DMA stiffness constant (half an order of magnitude) which was quite unexpected. DNA bending up to 150° on the 5 nm length scale requires on average 12 kcal/mol. It is slightly less expensive, -10 kcal/mol when a run of consecutive adenines is present. Methodological development of Hamiltonian replica exchange sampling techniques enables to characterize several competing DNA backbone conformations accessible to damaged DNA (an abasic site). More generally the PhD thesis presents the development of new methods to tackle the accurate sampling of particular nucleic acid helical propensities, and this is closed with a brief section on an original effort to create a self-learning approach in the context of replica exchange sampling with molecular dynamics
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Wu, Zhanghan. "Understanding molecular and cellular processes using statistical physics." Diss., Virginia Tech, 2011. http://hdl.handle.net/10919/27745.
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Using statistical physics principles to solve problems in biology is one of the most promising directions due to the complexity and non-equilibrium fluctuations in biological systems. In this work, we try to describe the dynamics at both cellular and molecular levels. Microtubule dynamics and dynamic disorder of enzyme proteins are two of the examples we investigated. The dynamics of microtubules and the mechanical properties of these polymers are essential for many key cellular processes. However, critical discrepancies between experimental observations and existing models need to be resolved before further progress towards a complete model can be made. We carried out computational studies to compare the mechanical properties of two alternative models, one corresponding to the existing, conventional model, and the other considering an additional type of tubulin lateral interaction described in a cryo-EM structure of a proposed trapped intermediate in the microtubule assembly process. Our work indicates that a class of sheet structures is transiently trapped as an intermediate during the assembly process in physiological conditions. In the second part of the work, we analyzed enzyme slow conformational changes in the context of regulatory networks. A single enzymatic reaction with slow conformational changes can serve as a basic functional motif with properties normally discussed with larger networks in the field of systems biology. The work on slow enzyme dynamics fills the missing gap between studies on intramolecular and network dynamics. We also showed that enzyme fluctuations could be amplified into fluctuations in phosphorylation networks. This can be used as a novel biochemical â reporterâ for measuring single enzyme conformational fluctuation rates.<br>Ph. D.
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Westerlund, Annie M. "Computational Study of Calmodulin’s Ca2+-dependent Conformational Ensembles." Licentiate thesis, KTH, Biofysik, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-234888.
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Ca2+ and calmodulin play important roles in many physiologically crucial pathways. The conformational landscape of calmodulin is intriguing. Conformational changes allow for binding target-proteins, while binding Ca2+ yields population shifts within the landscape. Thus, target-proteins become Ca2+-sensitive upon calmodulin binding. Calmodulin regulates more than 300 target-proteins, and mutations are linked to lethal disorders. The mechanisms underlying Ca2+ and target-protein binding are complex and pose interesting questions. Such questions are typically addressed with experiments which fail to provide simultaneous molecular and dynamics insights. In this thesis, questions on binding mechanisms are probed with molecular dynamics simulations together with tailored unsupervised learning and data analysis. In Paper 1, a free energy landscape estimator based on Gaussian mixture models with cross-validation was developed and used to evaluate the efficiency of regular molecular dynamics compared to temperature-enhanced molecular dynamics. This comparison revealed interesting properties of the free energy landscapes, highlighting different behaviors of the Ca2+-bound and unbound calmodulin conformational ensembles. In Paper 2, spectral clustering was used to shed light on Ca2+ and target protein binding. With these tools, it was possible to characterize differences in target-protein binding depending on Ca2+-state as well as N-terminal or C-terminal lobe binding. This work invites data-driven analysis into the field of biomolecule molecular dynamics, provides further insight into calmodulin’s Ca2+ and targetprotein binding, and serves as a stepping-stone towards a complete understanding of calmodulin’s Ca2+-dependent conformational ensembles.<br><p>QC 20180912</p>
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Ahlstrom, Logan S., Ivan I. Vorontsov, Jun Shi, and Osamu Miyashita. "Effect of the Crystal Environment on Side-Chain Conformational Dynamics in Cyanovirin-N Investigated through Crystal and Solution Molecular Dynamics Simulations." PUBLIC LIBRARY SCIENCE, 2017. http://hdl.handle.net/10150/622743.
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Side chains in protein crystal structures are essential for understanding biochemical processes such as catalysis and molecular recognition. However, crystal packing could influence side-chain conformation and dynamics, thus complicating functional interpretations of available experimental structures. Here we investigate the effect of crystal packing on side-chain conformational dynamics with crystal and solution molecular dynamics simulations using Cyanovirin-N as a model system. Side-chain ensembles for solvent-exposed residues obtained from simulation largely reflect the conformations observed in the X-ray structure. This agreement is most striking for crystal-contacting residues during crystal simulation. Given the high level of correspondence between our simulations and the X-ray data, we compare side-chain ensembles in solution and crystal simulations. We observe large decreases in conformational entropy in the crystal for several long, polar and contacting residues on the protein surface. Such cases agree well with the average loss in conformational entropy per residue upon protein folding and are accompanied by a change in side-chain conformation. This finding supports the application of surface engineering to facilitate crystallization. Our simulation-based approach demonstrated here with Cyanovirin-N establishes a framework for quantitatively comparing side-chain ensembles in solution and in the crystal across a larger set of proteins to elucidate the effect of the crystal environment on protein conformations.
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Alibay, Irfan. "Development and application of an enhanced sampling molecular dynamics method to the conformational exploration of biologically relevant molecules." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/development-and-application-of-an-enhanced-sampling-molecular-dynamics-method-to-the-conformational-exploration-of-biologically-relevant-molecules(774ad8b6-d531-47c7-8892-59d52e66e56e).html.
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This thesis describes the development a new swarm-enhanced sampling methodology and its application to the exploration of biologically relevant molecules. First, the development of a new multi-dimensional swarm-enhanced sampling molecular dynamics (msesMD) approach is detailed. Relative to the original swarm-enhanced sampling molecular dynamics (sesMD) methodology, the msesMD method demonstrates improved parameter transferability, resulting in more extensive sampling when scaling to larger systems such as alanine heptapeptide. The implementation and optimisation of the swarm-enhanced sampling algorithms in the AMBER software suite are also described. Through the use of the newer pmemd molecular dynamics (MD) engine and asynchronous MPI routines, speedups of up to three times the original sesMD implementation were achieved. The msesMD method is then applied to the investigation of carbohydrates, first looking at rare conformational changes in Lewis oligosaccharides. Validating against multi-microsecond unbiased MD trajectories and other enhanced sampling methods, the msesMD simulations identified rare conformational changes leading to the adoption of non-canonical unstacked core trisaccharide structures. Next, the use of msesMD as a tool to probe pyranose ring pucker events is explored. Evaluating against four benchmark monosaccharide systems, msesMD simulations accurately recover puckering details not easily obtained via multi-microsecond unbiased MD. This was followed by an exploration of the impact of ring substituents on conformation in glycosaminoglycan monosaccharides: through msesMD simulations, the influence of specific sulfation patterns were explored, finding that in some cases, such as 4-O-sulfation in N-acetyl-galactosamine, large changes in the relative stability of ring conformers can arise. Finally, the msesMD method was coupled with a thermodynamic integration scheme and used to evaluate solvation free energies for small molecule systems. Comparing against independent trajectory TI simulations, it was found that although the correct solvation free energies were obtained, the msesMD based method did not offer an advantage over unbiased MD for these small molecule systems. However, interesting discrepancies in free energy estimates arising from the use of hydrogen mass repartitioning were found.
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Ghassemizadeh, Reyhaneh [Verfasser], and Michael [Akademischer Betreuer] Walter. "Ab initio study on molecular charge transport and conformational analysis of organic molecules." Freiburg : Universität, 2019. http://d-nb.info/1190560429/34.
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Curuksu, Jérémy [Verfasser]. "Conformational sampling by molecular mechanics and dynamics simulations applied to the flexibility of nucleic acids / Jérémy Curuksu." Bremen : IRC-Library, Information Resource Center der Jacobs University Bremen, 2009. http://d-nb.info/1034715429/34.
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Rahman, Kazi Shefaet. "Molecular modeling and simulations of the conformational changes underlying channel activity in CFTR." Diss., Georgia Institute of Technology, 2013. http://hdl.handle.net/1853/50346.
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Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) cause cystic fibrosis (CF), the most common life-shortening genetic disease among Caucasians. Although general features of the structure of CFTR have been predicted from homology models, the conformational changes that result in channel opening and closing have yet to be resolved. We created new closed- and open-state homology models of CFTR, and performed targeted molecular dynamics simulations of the conformational transitions in a channel opening event. The simulations predict a conformational wave that starts at the nucleotide binding domains and ends with the formation of an open conduction pathway. Experimentally confirmed changes in side-chain interactions are observed in all major domains of the protein. We also identified unique-to-CFTR substitutions that may have led to channel activity in CFTR. Molecular modeling and simulations are used to compare the effects of these substitutions against a canonical ABC transporter, and suggest that gain of channel function in CFTR may have risen from loss of ATPase function at its NBDs. The models and simulation add to our understanding of the mechanism of ATP-dependent gating in this disease-relevant ion channel.
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Foord, Elizabeth Kate. "The conformational analysis of small, flexible molecules using NMR of liquid crytalline solutions." Thesis, University of Southampton, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243148.
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Lockwood, Daren M. "Molecular dynamics investigations of protein volumetric properties and electronic dynamics /." Digital version accessible at:, 2000. http://wwwlib.umi.com/cr/utexas/main.
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Williams, Robert Keith. "Molecular conformational studies of deoxyribonucleic acid by potential energy minimization with normal mode analysis." Thesis, Keele University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292541.
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Cao, Jin. "Single Molecular Spectroscopy and Atomic Force Manipulation of Protein Conformation and Dynamics." Bowling Green State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1416588612.
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