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In the past sixty years, X-ray, neutron and electron dffraction have emerged as the structural techniques of choice in the solid state. However, despite many advances in theory and instrumentation, these diffraction methods are still reliant on a number of assumptions. Chief amongst these is that the atoms in the crystal vibrate in a harmonic fashion. This thesis is concerned with understanding the effects of anharmonic motion on crystal structure determination and developing new ways of moving beyond the harmonic approximation used in crystallography. A method has been developed, using molecular dynamics simulations, to correct experimental structures to equilibrium structures. This has been applied to the crystal structures of phase-I deutero-ammonia, deutero-nitromethane and benzophenone. Path-integral molecular dynamics simulations have been used to obtain meaningful comparison with experimental data collected at low temperatures. The simulations also offer information on the probability density functions that describe thermal motion in solids. Using data from simulations of nitromethane and other compounds it has been demonstrated that the molecular dynamics-derived data can be used to assess and develop new functions for modelling thermal motion in crystal structure refinements. Finally, similar molecular dynamics techniques have been applied to determine the equilibrium structures of some polyhedral oligomeric silsesquioxanes in the gas phase. Some members of this class of compounds feature such strong anharmonic motion that refinement of the structures using gas electron diffraction is impossible without taking into account the effects of the anharmonicity.

Master of Science / Department of Physics / Jeremy Schmit / Over twenty percent of amino acids are ionized under biological conditions, and the subsequent electrostatic interactions have substantial effect on protein crystallization, binding, catalyzation, and recognition. These electrostatics along with other intermolecular forces create a delicate balancing act of repulsive and attractive forces. This thesis explores the effects of electrostatics on the formation of dense ordered structures. In dense protein aggregates the repulsive electrostatics are dominated by the entropic cost of compressing salt ions in the electrostatic screening layer. A non-local electrostatic interaction was derived to describe this behavior, and was used to examine the interplay of attractive energies and repulsive entropy on protein colloid stability and the crystallization process. Using a simple analytical model it was predicted that the derived electrostatic effects describe a finite window in phase space in which crystallization can occur. This simple model was expanded upon via computational methods simulating hard spherical particles aggregating under short-ranged attractive interactions and the repulsive electrostatics. From the computational simulations phase and dynamical data was extracted to confirmed the initial insight of the analytical model. The simulations also introduced new information not described by the simple model, most notably a metastable amorphous phase caused by the competition of energies and entropies.

Thesis advisor: Goran Krilov / Solubilization and separation is an important step in utilizing both the unique mechanical and electrical properties of carbon nanotubes (CNTs). Due to different possible chiralities of CNTs, which can have drastically different electrochemical properties, it is also necessary to have a method of separation that will distinguish between these different species. Recent discovery of single-stranded DNA (ssDNA) absorption onto CNTs have shown high affinity towards forming soluble hybrids in polar solvents. The interactions between the ssDNA and CNTs as well as the geometry of the hybrid structure are not well understood. In order to study these phenomena we have implemented multiple all-atom replica exchange simulations. Simulations are carried out in an aqueous environment and vary in single-stranded decamer composition as well as nanotube chirality. The oligonucleotides readily adsorb onto the carbon nanotube surface and immediately following begin a slow structural rearrangement. Dependent upon both oligonucleotide composition and nanotube chirality, the ssDNA is found to form several unique backbone geometries as defined by both local and global order parameters. In contrast to the multiple geometries the backbone may form to, the nucleotide bases are found to organize themselves into either parallel or anti-parallel conformation with a high degree of orientational order. Binding appears to be mainly driven by π-stacking interactions between DNA bases onto the carbon nanotube surface, equilibrium of the structures is also controlled by a complex mixture of forces including DNA conformational strain and solvent interactions. The result of this is the free energy landscape is found to have multiple minima occupied at room temperature which are separated by high energy barriers. / Thesis (MS) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Nucleation is the process by which a metastable phase decays into a stable phase. It is widely observed in nature, and is responsible for many phenomena such as the formation clouds and domains in crystalline solids. The classical theory of nucleation predicts that the objects that initiate the decay from the metastable to the stable phase are compact droplets whose interior has the structure of the stable phase. For quenches deep into the metastable phase, however, the droplets may be ramified, with a structure very different from the stable phase. This difference has profound implications for material properties, especially because predicting the onset of structure early enough is useful for manipulating and controlling nucleation processes. I used molecular dynamics to simulate nucleation in Lennard-Jonesium, a model system for liquid-solid transformations. The system is quenched from a high temperature, where the liquid is stable, to a temperature where the liquid is metastable, and is allowed to nucleate via fluctuation-driven clusters referred to as critical droplets. I determined the occurrence of critical droplets by the intervention method, but found a non-monotonic variation in droplet survival rates near the saddle point. I determined the structure of the critical droplet and found evidence for a core consisting of mostly solid-like particles with hcp symmetry and a previously unknown planar structure around it. Using perturbative techniques, I showed that the planar particles have a significant influence on the nucleation and growth of critical droplets. I also introduced a novel method of learning symmetries to predict the structure and appearance of precursors to the critical nucleus. My results give added evidence for the presence of spinodal nucleation at deep quenches.

Les microtubules sont des polymères cylindriques de tubuline-αβ, membres du cytosquelette eucaryote. Ils possèdent une dynamique intrinsèque nécessaire à de nombreuses fonctions cellulaires telle que la mitose. L’hydrolyse du nucléotide GTP dans les polymères de tubuline-αβ ainsi que les interactions entre la tubuline et les protéines partenaires ou les molécules à visées pharmacologiques, jouent un rôle critique sur la dynamique des microtubules. Durant cette thèse, des approches de modélisation moléculaire ont été utilisées pour mieux appréhender les interactions tubuline-ligand à l’échelle atomique et contribuer au développement de nouvelles molécules actives. Des simulations de dynamiques moléculaires ont été réalisées pour étudier l’effet de différents nucléotides dans la tubuline-β sur la structure et la dynamique du protofilament de tubuline. Nous proposons un rôle du résidu αE254 dans la coordination du magnésium catalytique. Nous observons également des changements conformationnels aux interfaces latérales et un réarrangement de structure aux interfaces longitudinales qui peuvent affecter la stabilisation du microtubule. Des travaux menés au laboratoire ont montré que la colchicine et le carbendazime se fixent dans des poches voisines dans la sous-unité tubuline-β et inhibent la prolifération cellulaire. Nous avons proposé un site de fixation du carbendazime dans les complexes tubuline-colchicine à l’aide de l’amarrage moléculaire et de simulations de dynamiques moléculaires. Ces expériences ont mené au design de molécules hybrides composées des noyaux colchicine et carbendazime reliés par un linker. Une de ces molécules hybrides a été synthétisée et testée avec succès sur des lignées de cellules HeLa. Enfin, nous avons construit des peptides cycliques dérivées d’I19L, un peptide anti-microtubule identifié au laboratoire. Des simulations de dynamique moléculaire et des calculs d’énergie libre de liaisons ont permis d’évaluer ces peptides. Enfin, des mutations ont été proposées afin d’optimiser l’interaction entre le meilleur peptide et la tubuline. / Microtubules are cylindrical polymers of αβ-tubulin heterodimers, members of the eukaryotic cytoskeleton. They possess an intrinsic dynamics which is necessary to any cellular functions such as the mitosis. It has long been recognized that GTP hydrolysis in αβ-tubulin polymers plays a critical role in this dynamics as well as the interactions between tubulin and the protein partners or the drugs. In this thesis, molecular modeling approaches are applied to three theoretical studies to gain insight at the atomic scale about tubulin-ligand interactions and to contribute to the development of new active compounds. Molecular dynamics simulations were used to study the effect of the different nucleotide states at β-tubulin on the protofilament structure and dynamics. We propose a role for residue αE254 in catalytic magnesium coordination. We also observe conformational changes and structure rearrangement at lateral and longitudinal interfaces that can affect the microtubule stabilization. Previous work carried out in the laboratory showed that colchicine and carbendazime bind neighboring pockets in the β-tubulin subunit and inhibit cell proliferation. We proposed a binding site of carbendazime on the tubulin-colchicine complex, using docking and molecular dynamics simulation, which lead to the design of hybrid molecules composed of both colchicines and carbendazime moieties attached with a linker. One of these hybrid molecules has been synthesized and successfully tested on HeLa cells. Finally, we designed four cyclic peptides based on I19L, an anti-microtubule peptide identified at the laboratory. Molecular dynamic simulations and binding free energy calculations were used to evaluate these peptides. Mutations were then proposed on the best peptide to increase its interactions with tubulin.

Computer simulations allow researchers to study the dynamics and interactions of biological molecules in ways that cannot be currently achieved in experiments. In this work, I have used computer simulations to study the following systems: (1) carbohydrate-carbohydrate and carbohydrate-amino acid interactions using all-atom molecular dynamics simulations, and (2) protein-protein interactions using coarse-grained implicit solvent models. My first studies involved simulating carbohydrate and amino acid systems using atomistic force fields. During my initial simulations, I observed that carbohydrates were interacting too favorably leading them to aggregate in conditions under which they experimentally remain soluble. To alleviate this issue, I surgically modified the carbohydrate-carbohydrate interaction parameters in order to match osmotic pressure data from experiment. This approach was successful while preserving many of the correct features of the original force field. Next, I observed similar issues in carbohydrate-amino acid simulations and used the same methodology to correct carbohydrate-amino acid parameters. I showed that the modified parameters also worked well in simulations of much larger systems, allowing realistic simulations to be performed on polymeric sugars such as dextran and the peptidoglycan layer of the cell wall. In a more recent and separate study, I have attempted to parameterize very coarse-grained models of proteins (for eventual use in cellular scale simulations) using experimental osmotic second virial coefficients. I found that a 10 residue-per-bead model including electrostatic interactions could approximately match most of the second virial coefficient data obtained from experiment. In contrast, a more simplified, spherical model of proteins could not adequately reproduce experiment. Although more work will be required to establish a better quantitative agreement with experiment, my results indicate that even very coarse models of proteins can produce reasonably accurate simulations of protein-protein interactions.

Thesis (Ph. D.)--University of Nevada, Reno, 2005. / "December 2005." Includes bibliographical references. Online version available on the World Wide Web.

In this study, the molecular dynamics simulation method was used to investigate the mechanical properties of non-crystalline PEEK mixed with SiO2 nanoparticle. It is found the SiO2/PEEK nano-composite has higher mechanical properties in comparison with pure PEEK composite. Therefore, we wish to obtain the reason. The radial distribution function was used to explain the conformation of the change of microstructure and mechanical properties. The parametric study of different SiO2 particle size was discussed, such on the effects on the structure of PEEK and the strength of the structure.