Dissertations / Theses on the topic 'Conformation of molecules'

Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2008.<br>Committee Chair: Zhu, Cheng; Committee Member: Babensee , Julia; Committee Member: Garcia, Andres; Committee Member: McIntire, Larry; Committee Member: Selvaraj, Periasamy; Committee Member: Springer, Timothy

This paper presents the results of investigations of the influence of the longitudinal and transverse electric field on the potential surface, the dipole moment and electronic spectra of the substituted biphenyl molecules that are offered for the role of the elements of nanoelectronics. When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/35480

Small molecule mediated chemical intervention of biological processes using nucleic acid targets has proven extremely successful and is continually providing exciting new avenues for the development of anti-cancer agents and molecular probes. Among the alternative DNA confrormations, G-quadruplexes has certainly garnered much recognition due to increase in evidences supporting their involvement in diverse biological process. The grooves of the quadruplexes offer an alternate recognition site for ligand interactions with potentially higher selectivity than the traditional terminal stacking sites. DB832, a bifuryl-phenyl diamidine, was recently reported to selectively recognize human telomeric G-quadruplex, as a stacked species, with significant selectivity over duplex sequences. A series of biophysical studies were conducted to test the groove-binding mode of DB832, along with the selectivity for diverse quadruplex forming sequences. To gain better understanding of quadruplex groove-recognition by DB832, a series of structurally similar heterocyclic diamidines were also evaluated. The unique binding mode of DB832 may allow it to serve as a paradigm for the design of new class of highly selective quadruplex groove-binding molecules. Beyond the alternative secondary structures, it is also becoming increasingly apparent that the structure and dynamics of the canonical Watson–Crick DNA double helix play pivotal roles in diverse biological functions. DB1878, a phenyl-furan-indole diamidine, was shown to recognize a mixed GC/AT motif as a stacked antiparallel dimer, and a detailed structural analysis is reported here. Interestingly, the DNA recognition is completely different from the reported molecules in literature, and represents an entirely new motif for DNA minor groove recognition.

Synthese du polydimethylsiloxane etudie et etude de l'hydrosilation se produisant au cours de la reticulation en solution semidiluee, relation entre la longueur de correlation et la concentration. Interactions a trois corps dans le styrene, solvant theta du pdmsi

NMR spectroscopy in liquid crystal solutions of polypeptides has been used for almost two decades, and has been shown to be a useful technique for the structure determination and the chiral discrimination of organic solutes. However the underlying mechanism remains largely unknown and there are several open questions. They concern the nature of the forces which control the anisotropic distribution of solutes: are there specific interactions, like hydrogen bonds, which involve selected chemical groups? Also the effects of co-solvent and temperature are scarcely understood: do they control the polypeptide-solute interactions or do they play an indirect role, by affecting the structure of the polypeptide? The lack of knowledge is a limit for the full exploitation of the NMR technique in liquid crystals. A deeper insight would be important to guide the optimization of the working conditions, e.g. by a proper selection of the polypeptide/co-solvent pair, given the nature of the solute. Especially challenging is the phenomenon of chiral discrimination. It occurs because pairs of enantiomers interacting with chiral polypeptides form diastereoisomeric pairs, but the forces relevant to this purpose are not known. In this thesis the behaviour of solutes in ordered solutions of poly(γ-benzyl-glutamate) (PBG) has been investigated using computational methods. The theoretical work has been carried out in close connection with experimentalists, from the laboratory of the Laboratoire de RMN en Milieu Orienté, Institut de Chimie Moléculaire d’Orsay de l’Université de Paris Sud, 11 (ICMMO) where a peculiar expertise in NMR techniques in liquid crystal media has been developed. Theoretical results have been checked against NMR data; moreover, new measurements have been performed in parallel with the computational study, to control the consistency of theoretical and experimental results. A major objective of this thesis has been the development of new computational tools for the analysis of experimental data, with the two-fold purpose of (i) helping the spectral interpretation and (ii) extracting the structural information which is contained in experimental data. In this thesis we have explicitly considered natural abundance deuterium (NAD) 2D-NMR experiments, so we have focussed on 2H-quadrupolar splittings; however the methods used here could be extended to other kinds of magnetic interactions. We have used different approaches to address the problems of chiral discrimination and structure determination. Chiral discrimination has been studied by fully atomistic Molecular Dynamics (MD) simulations. This level is needed, since the difference of orientational order, and then the spectral differences, between enantiomers is extremely small and depends on details of the intermolecular potentials. This is a general feature of chiral properties, which result from a subtle balance of energetically comparable contributions. This study had first of all an explorative purpose: it had to be assessed whether methods based on empirical intermolecular potentials could provide reliable information on chiral properties. A few solutes were investigated, but most of the work focussed on the prochiral molecule benzyl alcohol (BZA), which was found to be particularly appropriate for two main reasons. First, it exhibits a large difference in the 2H quadrupolar splittings of the two enantiotopic directions; moreover, it can be used as co-solvent, and this can be to improve the sampling efficiency in MD simulations. The problem of structural analysis is comparably less delicate, because the experimental differences in orientational order between molecules with different chemical structure are relatively larger. From the theoretical point of view, this means that approximate models can be developed, which are useful to rationalize the mechanism of solute ordering. Moreover, the availability of less demanding approaches, able to provide reliable predictions of order parameters, and then patterns of 2H-NMR splittings, at a relatively low computational cost, is essential for the development of computational tools to be used in connection with experiments. The thesis is divided in two parts. The first part is dedicated to the problem of structure analysis. In chapter 3 the so called tube model will be presented, for the calculation of the deuterium quadrupolar splittings of a solute on the basis of its chemical structure, under the assumption of simple steric repulsions with the polypeptide. The subsequent chapter 4 illustrates the computational methodologies which have been developed to predict the deuterium quadrupolar splitting profiles for flexible solutes, using the tube model coupled with suitable sampling of molecular conformations. Chapter 5 reports the experimental and theoretical study of a series of saturated fatty acid methyl esters (C14 –18). Chapter 6 presents a systematic study of saturated, unsaturated and conjugated fatty acid methyl esters and shows how torsional parameters can be extracted from the 2H quadrupolar splitting profiles. The second part of the thesis deals with chiral discrimination. In chapter 7 the results of a series of NAD 2D-NMR experiments on BZA, carried out at the ICMMO will be summarized. Then, chapter 8 is dedicated to Molecular Dynamics simulations. First the preliminary study of PBLG in chloroform will be presented, which was used to validate the parameterization of the force field for this polypeptide. Then, the results obtained for BZA in binary and ternary mixtures will be reported.<br>La spettroscopia NMR in soluzioni liquido cristalline di polipeptidi è utilizzata da una ventina d’anni e si è rivelata applicabile con ottimi risultati, sia per la determinazione strutturale, si per la discriminazione chirale di molecole organiche. Tuttavia il meccanismo che ne sta alla base rimane poco chiaro e ci sono molte questioni irrisolte. Queste riguardano la natura delle forze che controllano la distribuzione anisotropica dei soluti; non si conosce, ad esempio, quale possa essere il ruolo di interazioni specifiche, come legami idrogeno. Inoltre gli effetti del cosolvente e della temperatura non sono chiari, non si è capito se incidano direttamente sulle interazioni soluto-peptide oppure se abbiano un effetto indiretto, andando a modificare la struttura del polipeptide stesso. La scarsa comprensione costituisce un limite che impedisce di sfruttare appieno le potenzialità della tecnica NMR in cristalli liquidi. Una maggiore padronanza del fenomeno sarebbe un importante punto di partenza per ottimizzare le condizioni di lavoro; ad esempio si potrebbe scegliere con più cognizione il sistema peptide-cosolvente ideale per un determinato soluto. Un aspetto particolarmente interessante riguarda la discriminazione chirale: si sa che avviene perché l’interazione di coppie di enantiomeri con i polipeptidi chirali origina coppie di diastereoisomeri, ma non è noto quali forze ne siano responsabili. In questa tesi si è studiato il comportamento di soluzioni liquido-cristalline di poli(γ-benzil-glutammato) utilizzando metodi computazionali. Il lavoro teorico è stato svolto in collaborazione con un gruppo sperimentale del laboratorio del Laboratoire de RMN en Milieu Orienté, Institut de Chimie Moléculaire d’Orsay de l’Université de Paris Sud, 11 (ICMMO), che ha sviluppato una competenza specifica nelle tecniche NMR in fasi di cristallo liquido. I risultati teorici sono stati confrontati con quelli dati NMR; inoltre, in parallelo ai calcoli, sono stati eseguiti nuovi esperimenti, in modo tale da controllare la consistenza tra risultati teorici e sperimentali. Uno degli obiettivi principali della tesi è stato quello di sviluppare nuovi strumenti computazionali per l’analisi dei dati sperimentali con il duplice scopo di (i) essere un supporto per l’interpretazione spettrale e (ii) estrarre le informazioni strutturali contenute nei dati sperimentali. Nella tesi si è fatto esplicito riferimento a esperimenti in abbondanza naturale di deuterio (NAD 2D-NMR), perciò ci si è focalizzati su splitting quadrupolari di deuterio; tuttavia i metodi utilizzati possono essere estesi ad altri tipi di interazioni amgnetiche. Si sono utilizzati approcci diversi per affrontare il problema della discriminazione chirale e quello dell’analisi strutturale. I meccanismi che portano a discriminazione chirale sono stati investigati attraverso simulazioni di Dinamica Molecolare (MD) a livello atomistico. La scelta è stata dettata dalla constatazione che le differenze di ordine orientazionale, e quindi le differenze spettrali, tra coppie di enantiomeri sono molto piccole e possono dipendere da dettagli delle interazioni intermolecolari. Questa è una caratteristica fondamentale delle proprietà chirali, che sono il risultato di un bilanciamento delicato di contributi energetici di entità comparabile comparabili. Innanzitutto lo studio ha avuto uno scopo esplorativo: si è voluto valutare se metodi basati su potenziali intermolecolari empirici possano fornire informazioni affidabili di proprietà chirali in fase condensata. Sono stati studiati alcuni soluti, ma la maggior parte del lavoro si è concentrata sull’alcol benzilico (BZA), una molecola prochirale che si è rivelata particolarmente adatta allo scopo per più di un motivo. Innanzitutto essa presenta una differenza relativamente grande tra gli splitting quadrupolari di deuterio per le due direzioni enantiotopiche; inoltre ha il vantaggio di potere essere usata come solvente, e questo permette di aumentare l’efficienza del campionamento nelle simulazioni MD. Per quanto riguarda la determinazione strutturale, il problema è meno delicato in quanto le differenze sperimentali tra i parametri d’ordine di molecole con strutture diverse sono relativamente più grandi. Ciò significa che dal punto di vista teorico è possibile sviluppare modelli approssimati, che sono utili per razionalizzare il meccanismo alla base dell’ordine dei soluti. Inoltre la possibilità di mettere a punto approcci in grado di fornire stime dei parametri d’ordine, e quindi pattern di splitting quadrupolari, a un costo computazionale non troppo elevato, è essenziale per lo sviluppo di metodologie integrate con gli esperimenti. Questa tesi è quindi sviluppata in due parti. Nella prima parte ci si è concentrati sul problema della determinazione strutturale. Nel capitolo 3 viene presentato il modello del cilindro rigido, che permette di calcolare gli splitting quadrupolari di un soluto sulla base della sua struttura, partendo dall’ipotesi che le interazioni soluto-polipeptide siano essenzialmente di tipo sterico. Nel capitolo 4 sono riportate le metodologie computazionali sviluppate per il calcolo dei profili di splitting quadrupolari di soluti flessibili, utilizzando il modello del cilindro rigido accoppiato con un campionamento adeguato dello spazio conformazionale. Nel capitolo 5 si trova l’applicazione di questo metodo ad una serie di esteri metilici di acidi grassi saturi (C14-C18). Il capitolo 6 riporta uno studio sistematico di esteri di acidi grassi saturi, insaturi e insaturi coniugati, nel quale si mostra come i parametri torsionali possono essere estrapolati dal profilo degli splitting quadrupolari. La seconda parte della tesi riguarda la discriminazione chirale. Nel capitolo 7 si riportano i risultati di una serie sistematica di esperimenti NMR sull’alcol benzilico, condotti presso i laboratori dell’ICMMO. Il capitolo 8 è invece dedicato alle simulazioni di Dinamica Molecolare. Innanzitutto viene presentato uno studio preliminare sul PBLG in cloroformio, eseguito per validare la parametrizzazione del campo di forze utilizzato per questo polipeptide. Quindi sono riportati i risultati ottenuti per l’alcol benzilico in miscele liquido-cristalline binarie e ternarie.

Thesis (Ph.D.)--Chemical Engineering, Georgia Institute of Technology, 2009.<br>Committee Chair: Peter Ludovice; Committee Member: Amyn Teja; Committee Member: Arthur Ragauskas; Committee Member: William Koros; Committee Member: Yulin Deng.

In dieser Arbeit wurden auf Substratoberflächen adsorbierte Polymermoleküle mit Rasterkraftmikroskopie (RKM) untersucht. Dabei war die Form der Moleküle (Konformation) von besonderem Interesse. Sie ist von zentralerer Bedeutung in der Polymerphysik und wird üblicherweise in Lösung und mit Streumethoden untersucht. Polymerkonformationen auf Oberflächen sind heutzutage noch wenig untersucht. Üblicherweise wird das Verhalten nach dem so genannten Wormlike-Chain Modell angenommen. Es basiert auf der Annahme, dass die Kettenbiegung nur aus thermischen Fluktuationen resultiert, so dass sich die Kettenform durch statistische Mechanik beschreiben lässt. Es wurden für verschiedene Modellsystem einzelne Moleküle hochaufgelöst abgebildet und die Konformation aus den Bildern bestimmt. Es hat sich gezeigt, dass die idealisierte Vorstellung des Wormlike-Chain Modells tatsächlich nur für wenige der untersuchten Systeme erfüllt ist. Abweichende Konformationen sind oft auffallend regelmäßig: entweder sinusartig mäandrierte oder spiralförmig gedrehte. Beide Charakteristika lassen sich aus dem Prozess der Adsorption erklären, was zeigt, dass die Moleküle auf dem Substrat immobil sind, so dass eine thermische Relaxation der Konformation verhindert ist. Konformtionen lassen sich mit RKM nicht nur beobachten, sondern auch gezielt verändern (Nanomanipulation). Für dendronisierte Polymere konnte so gezeigt werden, dass es einen glasartigen Zustand für das einzelne Molekül gibt. In diesem Zustand verhält sich das Molekül nicht mehr wie eine bewegliche Kette, sondern formstabil, ähnlich einem makroskopischen festen Körper.<br>In this work single polymer molecules adsorbed onto substrate surfaces were investigated by scanning force microscopy (SFM). The focus was on the shape (conformation) of the molecules, which is of central importance in polymer physics. It is commonly investigated in solutions and with scattering methods. Conformations on surfaces are only little investigated thus far. Often a behavior according to the so-called worm-like chain model is assumed. It is based on the assumption that chain bending results entirely from thermal fluctuations so that the overall chain shape can be described by statistical mechanics. For several model systems single molecules were imaged and the conformation was determined from the images. It was found that the idealistic wormlike chain behavior is only valid for a few systems. Deviations are often remarkable regular: either sine-like undulated or spiral wound. Both characteristics can be explained from the process of adsorption, indicating that molecules are immobile on the substrate so that thermal relaxation is inhibited. Conformations can not only be imaged using the SFM, but also changed in a defined way (nanomanipulation). Manipulation experiments with dendronized polymers the existence of a glassy state for the single polymer. In this state the molecule no longer behaves as a flexible chain but remains its shape, similar to a macroscopic solid body.

La spectroscopie RMN alliée à l’utilisation de solvants cristal-liquide fortement et faiblement orientants est une stratégie efficace pour élucider les structures et distributions conformationnelles de petites molécules organiques rigides et flexibles en solution, et déterminer les ordres orientationnel et positionnel des solutés comme des solvants orientés. Dans une première partie, afin d’explorer les différentes contributions aux couplages dipolaires d’un soluté donné, la très faible amplitude de l’ordre orientationnel d’une molécule quasi-sphérique, le tetramethylallène, dissoute dans un nématique thermotrope est exploitée. Dans cette situation limite, le caractère prédominant des mécanismes de réorientation et de vibration moléculaire est mis en évidence, et estimé. Dans une seconde partie, les données RMN obtenues à partir de solutés de petites tailles dissous dans des solvants smectiques sont combinées aux résultats de calculs reposant sur des concepts de thermodynamique statistique et de la théorie de la fonctionnelle de densité. L’efficacité de cette méthode dans la détermination des paramètres d’ordres positionnel du solvant et orientationnel des molécules-sondes est démontrée aussi bien dans le cas de phases conventionnelles smectiques A que celui plus délicat de smectiques interdigitées Ad. La stratégie d’analyse proposée est ensuite étendue à l’investigation des structures tridimensionnelles et équilibres conformationnels de molécules flexibles bioactives ou biomimétiques. Dans une perspective méthodologique, à l’aide d’études expérimentale et théorique portant sur le biphényle, molécule symétrique constituée d’un unique rotor, il est tout d’abord démontré l’intérêt des méthodes de simulations par dynamique moléculaire pour évaluer l’ensemble des couplages dipolaires d’un soluté donné dans une phase thermotrope, ultérieurement utilisés comme paramètres initiaux dans une analyse spectrale itérative, et in fine déterminées précisément. L’analyse spectrale chronophage et dont l’aboutissement est incertain si les paramètres initiaux sont difficiles à estimer, en est ainsi facilitée. Puis, les distributions conformationnelles d’anti-inflammatoires non stéroïdiens de dérivés salicylés et profènes, fluorés ou non, constitués d’un ou deux rotors indépendants sont présentées. Via l’utilisation inédite du modèle AP-DPD dans les solvants nématiques (chiraux) lyotropes faiblement orientants, et à partir des couplages dipolaires homo- et hétéronucléaires notamment obtenus grâce à l’expérience RMN GET-SERF, créée à propos pour permettre l’extraction simple et rapide des couplages 1H-19F, les surfaces d’énergie potentielle de ces biomolécules sont décrites de façon satisfaisante. Enfin, les équilibres conformationnels de deux stilbénoïdes constitués de deux rotors coopératifs sont déterminés dans deux solvants cristal-liquide, l’un fortement, l’autre faiblement orientant. Ces études comparatives permettent de discuter la fiabilité, la précision et l’accessibilité des observables RMN extraites dans les phases, et d’établir la complémentarité des analyses RMN réalisées dans ces solvants<br>NMR spectroscopy in weakly and highly orienting media is used as a route for dealing with orientational, positional, structural and conformational problems of a variety of small rigid and flexible organic molecules in solution. First, the very weak orientational order of a quasi-spherical molecule dissolved in a nematic phase is exploited for exploring the role of the different contributions to the observed dipolar coupling. In such a limit condition, a predominant effect of the non-rigid reorientation-vibration coupling term emerges. Then, NMR data obtained from small rigid probes dissolved in smectic solvents are combined with a statistical thermodynamic density functional theory, in order to measure the positional order parameters of both solutes and solvent. The methodology gives good results when applied to a conventional smectic A liquid crystal and to the more delicate case of an interdigitated smectic Ad phase. The strategy is subsequently extended to the investigation of structure, order and conformational equilibrium of flexible bioactive or biomimetic molecules dissolved in various partially ordered NMR solvents. A first experimental and theoretical study is presented on the symmetric single-rotor molecule of biphenyl dissolved in a thermotropic liquid crystal. This test-case indicates molecular dynamics simulations are a promising tool for estimating a set of dipolar couplings of a solute in a thermotropic solvent, to be used as starting set of parameters in a standard operator-mediated NMR spectral analysis. Then, we report the conformational study of some single- and two-rotor nonsteroidal anti-inflammatory drugs, belonging to the families of salicylates and profens, dissolved in weakly orienting chiral nematic PBLG phases. A new pulse sequence, the Gradient Encoded heTeronuclear 1H-19F SElective ReFocusing NMR experiment (GET-SERF), is proposed here for the trivial edition of all 1H-19F couplings in one single NMR experiment, for a given fluorine atom. Starting from homo- and heteronuclear dipolar couplings, difficult to extract in thermotropic solvents because of a too complex spectral analysis, the torsional distributions of such molecules can be satisfactory described by the Additive Potential model combined with the Direct Probability Description of the torsional distribution in terms of Gaussian functions (AP-DPD approach). Finally, the conformational and orientational study of two stilbenoids displaying cooperative torsions is discussed in both a highly and weakly ordering liquid crystal phase. This comparative study allows to draw some conclusions on reliability, accuracy and accessibility of desired data in the two phases. Overall, this work proves NMR in liquid crystals is a flexible and meaningful tool for studying order, structure and conformation and it can greatly benefit from the availability of several aligning media inducing a different degree of order

Les protéines et acides ribonucléiques sont les principaux acteurs de nombreux processus cellulaires.Comprendre leurs fonctions, structures et interactions est un challenge important.Les méthodes expérimentales fournissent des informations sur la structure et la dynamique des molécules.Cependant les méthodes expérimentales sont limitées par le nombre de molécules qu'elles peuvent observer et les moyens qu'elles requièrent.Les méthodes de prédiction permettent d'obtenir des informations structurelles de façon quasi-automatique.Pour s'assurer de leur fiabilité, elles sont testées sur des données expérimentales.Nous présentons une procédure basée sur la cinétique inverse pour trouver une transition entre deux conformations d'un ARN tout en conservant sa structure secondaire.Nous obtenons des résultats comparables à l'état de l'art, ce qui montre que notre sélection des degrés de liberté est pertinente.De plus, nous utilisons des données partielles, ce qui permet d'utiliser différents types de résultats expérimentaux.Nous abordons aussi le problème du repliement protéique par une approche de théorie des jeux.Nous représentons une protéine par un jeu où les joueurs sont les acides aminés et les stratégies, les angles dièdres.La prédiction de structure peut alors être vue comme la recherche d'un équilibre dans un jeu multi-joueur où les fonctions d'utilité correspondent à la qualité du repliement.Nous montrons que l'algorithme de non-regret, appelé Hedge, garantit l'élimination des stratégies dominées et la convergence locale vers un équilibre de Nash.Puis, en limitant notre analyse aux jeux de potentiel, nous montrons qu'une classe plus large d'algorithmes, les algorithmes de régularisation, convergent vers un équilibre de Nash presque surement<br>Proteins and Ribonucleic Acids are the workhorses of many cellular processes.Understanding their functions, structures and interactions is an important challenge.Experimental methods provide actual information on structure and dynamics of molecules.However they have limitations : they cannot be applied to all molecules, and they need a lot of resources.Prediction methods are almost automatic ways of obtaining structural information.They are tested on experimental data to attest their reliability.We present, here, approaches tackling different problems.We develop a kinematics-based procedure to morph a RNA molecule between conformations while preserving its secondary structure.We obtain results comparable to state of the art methods showing that our selection of degrees of freedom is efficient.Furthermore we only use sparse information allowing for various kinds of experimental inputs.We also look at the protein structure prediction problem from a game theory angle.We represent the protein dynamics as a game, in which players are amino acids and strategies are dihedrals angles.The structure prediction can thus be seen as finding equilibrium in a multi-players game where all players have utility functions corresponding to the quality of the protein structure.We showed that a well-known no-regret algorithm, called Hedge, guarantees dominated strategies to vanish and a local convergence toward Nash equilibria.Furthermore restricting our analysis to potential games we showed that dual-averaging regularized learning algorithms converge toward a Nash equilibrium almost surely

Funktionalisierte organische Perylenbisimidfarbstoffe (PBI) und aus Cadmiumselenid bestehende Halbleiternanokristalle werden hinsichtlich physikalischer sowie chemischer Wechselwirkungsprozesse miteinander und mit ihrer Umgebung mittels zeitaufgelöster optischer Spektroskopie untersucht. Im Mittelpunkt der Studien an diesem organisch/anorganischen Modellsystem nanoskopischer Größe steht die Aggregatbildungskinetik und die Identifikation und Quantifizierung von Transferpozessen. Die Anbindung der gut löslichen PBI-Farbstoffe an die Oberfläche solcher Halbleiternanokristalle mittels spezieller Ankergruppen wird durch Selbstorganisation in Lösung realisiert. Die Kombination von Absorptions- und zeitaufgelöster Fluoreszenzspektroskopie zeigt einen unterschiedlich starken Einfluss von Liganden und Farbstoffen auf die Fluoreszenzlöschung der Nanokristalle und belegt, dass Resonanzenergietransfer zum Farbstoff nur in sehr geringem Maße die physikalische Ursache der Fluoreszenzlöschung ist. Die Anzahl adsorbierter Farbstoffe und die Stärke der Fluoreszenzlöschung eines einzelnen Farbstoffmoleküls werden aus zeitaufgelösten Einzelmolekülexperimenten an immobilisierten Emittern gewonnen, welche den direkten spektroskopischen Zugang zur Verteilung gebundener und freier Farbstoffe/Nanokristalle erlaubt. Darüber hinaus werden ankergruppen- und umgebungsspezifische Einflüsse auf die Konformations- und Orientierungsdynamik von Perylenbisimidmolekülen dargestellt. Abschließend werden photo-physikalische Gemeinsamkeiten chemisch unterschiedlich hervorgerufener Fluoreszenzlöschungsprozesse herausgearbeitet und im Kontext von Einzelkristall-Blinkprozessen diskutiert.

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.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2000.<br>Includes bibliographical references (p. 126-130).<br>This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.<br>The determination of molecular structures is of growing importance in modern chemistry and biology. This thesis presents two practical, systematic algorithms for two structure determination problems. Both algorithms are branch-and-bound techniques adapted to their respective domains. The first problem is the determination of structures of multimers given rigid monomer structures and (potentially ambiguous) intermolecular distance measurements. In other words, we need to find the the transformations to produce the packing interfaces. A substantial difficulty results from ambiguities in assigning intermolecular distance measurements (from NMR, for example) to particular intermolecular interfaces in the structure. We present a rapid and efficient method to simultaneously solve the packing and the assignment problems. The algorithm, AmbiPack, uses a hierarchical division of the search space and the branch-and-bound algorithm to eliminate infeasible regions of the space and focus on the remaining space. The algorithm presented is guaranteed to find all solutions to a pre-determined resolution. The second problem is building a protein model from the initial three dimensional electron density distribution (density map) from X-ray crystallography. This problem is computationally challenging because proteins are extremely flexible.<br>(cont.) Our algorithm, ConfMatch, solves this "map interpretation" problem by matching a detailed conformation of the molecule to the density map (conformational matching). This "best match" structure is defined as one which maximizes the sum of the density at atom positions. The most important idea of ConfMatch is an efficient method for computing accurate bounds for branch-and-bound search. Confmatch relaxes the conformational matching problem, a problem which can only be solved in exponential time (NP-hard), into one which can be solved in polynomial time. The solution to the relaxed problem is a guaranteed upper bound for the conformational matching problem. In most empirical cases, these bounds are accurate enough to prune the search space dramatically, enabling ConfMatch to solve structures with more than 100 free dihedral angles.<br>by Cheuk-san (Edward) Wang.<br>Ph.D.

This thesis discusses the synthesis and structural analysis of molecules pertinent to current problems in the areas of biosynthesis, structure activity relationships and cell biology. Chapter one investigates the structure of an N-terminal blocked derivative of methionine <SUP>5 </SUP>enkephalin, in DMSO solution, using single and two dimensional nmr techniques. Analysis of the data using standard methods indicates the formation of a type I' beta turn centered around the two glycine residues. Chapter two deals with the development and optimisation of a synthesis of D,L tyrosine which is suitable for the incorporation of isotopic labels to give enriched species such as [2-<SUP>13</SUP>C, <SUP>15</SUP>N]tyrosine which is a potentially useful biosynthesis probe. Possible uses of the probe are discussed and three routes are described. The most successful route is based on a modification of the Strecker reaction. Chapter three describes the synthesis, purification and conformational analysis of a fifteen residue peptide corresponding to the signal sequence of the hemagglutinin protein of the influenza virus A/WSN/33, the portion of the polypeptide responsible for its targeting to the cell surface. Circular dichroism studies of this N-terminal peptide in various solvents indicate that the peptide forms a predominantly β-sheet structure in aqueous solution and in alcoholic solutions of low hydrophobicity, while preferentially adopting a helical structure in more lipophilic solvent systems. The relevance of this to targeting to the cell surface is discussed.

A new method for modifying the course of a molecular dynamics computer simulation is presented. Digitally Filtered Molecular Dynamics (DFMD) applies the well-established theory of digital filters to molecular dynamics simulations, enabling atomic motion to be enhanced or suppressed in a selective manner solely on the basis of frequency. The basic theory of digital filters and its application to molecular dynamics simulations is presented, together with the application of DFMD to the simple systems of single molecules of water and butane. The extension of the basic theory to the condensed phase is then described followed by its application to liquid phase butane and the Syrian hamster prion protein. The high degree of selectivity and control offered by DFMD, and its ability to enhance the rate of conformational change in butane and in the prion protein, is demonstrated. The DFMD method is then modified and extended to become Reversible Digitally Filtered Molecular Dynamics (RDFMD). The RDFMD method improves the degree of control possible over that of DFMD. DFMD is applied to gas-phase pentane, alanine dipeptide, solvated alanine dipeptide and the pentapeptide YPGDV. In all four systems, RDFMD was able to enhance the rate of conformational change via reasonable transition paths. Finally, the new method of the Hilbert-Huang Transform (HHT) is described and applied to the analysis of conformational transitions. The HHT is shown to provide clear indications of the changes in energy and frequency during conformational transitions.

Stereochemistry is important aspect of chemistry that customarily includes the study of the relative spatial arrangement of atoms within molecules (static stereochemistry), and the study of the stereochemical requirements and outcomes of chemical reactions (dynamic stereochemistry). These two branches complement each other in modern stereochemistry. Chiral organometallics feature prominently in organic synthesis as reactive intermediates. The possibility of exploring their stereochemistry in synthesis is associated with the configurational stability of the metal-bearing stereogenic center. We were interested in the configurational stability of lithiated and magnesiated nitriles. We developed a new series of lithio-cyclopropylnitriles bearing chelating groups for intramolecular coordination, as a possible strategy to impart configurational stability. Although this strategy has not yet been successful, using density functional theory (DFT) method, we addressed the effect of chelating groups on racemization via the â conducted tourâ mechanism. We then explored metal-bromine exchange on enantiopure bromonitrile as alternative route to metalated nitriles. In this way, we demonstrated that magnesiated 2,2-diphenyl cyclopropylnitrile is configurationally stable on the macroscopic timescale. No other metallated nitrile has ever demonstrated configurational stability on this timescale. In contrast, bromine-lithium exchange of 1-bromo-2,2-diphenyl-cyclopropylnitrile demonstrated fast racemization under the same conditions. Another major project focused on conformational control of acyclic molecules. Using X-ray crystallography and NMR spectroscopy, we found that the 2,6-disubstituted aryl group eclipses its geminal hydrogen, and induces an antiperiplanar relationship of the geminal and vicinal hydrogens. Interestingly, anti-nitrile aldols or syn-ketone aldols bearing 2,6-disubstituted aryl groups demonstrate unanticipated remote effects on acyclic conformation: the 2,6-disubstituted aryl group prefers to be in a gauche position to the largest vicinal group. The minimization of allylic 1,3-strain and syn-pentane-like interaction works together in establishing this conformational preference.<br>Ph. D.

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.

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.<br>Title from electronic title page (viewed Mar. 27, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum in Applied and Materials Sciences." Discipline: Applied and Materials Sciences; Department/School: Applied and Materials Sciences.

In the present work the refinement of X-ray data have been used to solve different scientific problems, namely drug localization in the liposome wall, reaction kinetics of the small molecule upon excitation and resolving an ensemble of protein structures at different temperatures. The common approach included collection of X-ray scattering patterns, modelling of the system of interest in atomic level and fitting computed results to experimental data. Employed fitting algorithms varied depends on the application ranging from inverse matrix calculations to the genetic algorithm for complex tasks. Observed results broaden our understanding of investigated systems on molecular level and also lead to development faster, more effective ways to sample atomic structures by X-ray diffusion scattering.

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1995.<br>Includes bibliographical references (p. 45-47).<br>by Cheuk-san (Edward) Wang.<br>M.S.

In this dissertation, the introduction of the basic knowledge of microwave spectroscopy including the fundamental theory of the rotational spectroscopy and the experimental techniques was reviewed firstly. Then the work that I have performed during my PhD career is discussed. Pulsed-jet Fourier transform microwave (PJ-FTMW) spectroscopy has been used to study the monomers, and the bimolecular clusters formed with hydrogen bond or weakly non-covalent bonds. Difluoromethane and water oligomers have been studied by Chirped-Pulse Fourier transform microwave (CP-FTMW) spectroscopy. The spectroscopic work in this dissertation includes three parts: 1) Isolated molecules with large amplitude motions. Three subjects are involved in this part, which are the rotational studies of indan, 1,2-dimethoxylethane, and 1-methylcyclohexanol. The transitions were split due to ring puckering motion, the internal rotations of methyl groups, and the rotation of the hydroxyl group, respectively. 2) Clusters formed by the cooperation of different classes of HBs. Four subjects are involved in this chapter. Firstly, formic acid clustering with dimethyl ether and cyclobutanone, respectively, indicate that both complexes are formed with one typical O-H···O HB and two C-H···O weak hydrogen bonds (WHBs). Secondly, the investigation of the complex of indan with trifluoromethane showed a cage structure based on the cooperative effects of C-H···π and C-H···F WHB interactions. Lastly, The study of oligomers of (CH2F2)m-Wn, (m,n = 1,2) has broaden our knowledge of the cooperation of different HBs in a cluster. 3) Another interesting result is the observation of the competition between reactivity and the pre-reactivity in the mixtures of carboxylic acids and alcohols, which is a basic phenomenon in organic synthesis. The experimental results on the primary and secondary alcohols mixed with carboxylic acids have shown that the esterification reaction occurs, whereas only the spectra of the adducts could be identified by mixing the tertiary alcohols and formic acid.

The three-dimensional organization of the genome is important for various processes such as transcription, replication, and repair. Several studies have shown that the genome is organized into long-range and short-range chromatin loops. Gene loops represent a short-range chromatin loop, synonymous with the juxtaposition of promoter and terminator regions of a gene. In Chapter III, I investigate the mechanism of gene-loop formation in a constitutively expressed gene, mouse serum albumin (Alb). The Alb locus appears to exist in a clover-leaf structure, with the promoter in close physical proximity with an upstream enhancer and downstream genic sequences. Furthermore, Alb forms a promoter-terminator gene loop that is dependent on serine 2 phosphorylation of RNA polymerase C-terminal domain. I also investigate the presence of gene loop conformation at the human Nuclear factor NF-kappa-B (NFκB1) gene. In response to cytokine stimulation, NFκB1 transcription proceeds as a wave, with nascent RNA appearing as RNA polymerase traverses along the gene length. This coincides with formation of transient contacts between NFκB1 promoter and genic regions. The cohesin complex is a key mediator of chromatin loops and sister chromatid cohesion. The association of cohesin with chromatin is dependent on the loading complex, Mis4/Ssl3. In Chapter IV, I provide direct evidence for two functionally different populations of cohesin is Schizosaccharomyces pombe. Cohesin that co-localizes with Mis4 represents "cohesive" cohesin. In contrast, cohesin alone is unable to maintain stable sister chromatid cohesion, therefore, "less-cohesive" cohesin. Cohesive cohesin ensures stable cohesion because it is acetylated by the Eso1 acetyltransferase, which preferentially interacts with Mis4. In contrast, less-cohesive cohesin may function in recombination/repair. In Chapter V, I have identified a novel interplay between cohesin loading and transcription by RNA polymerase II. Inhibition of transcription initiation results in loss of Mis4 and consequently, cohesin binding on chromosomal arms regions. Furthermore, cohesin and Mis4 physically interact with RNA polymerase II. In Chapter VI, I summarize the above findings and propose a model that describes the stepwise loading of cohesin onto chromosomal arms during the fission yeast cell cycle. To conclude, I discuss the importance of understanding cohesin and its functions in health and diseases.