published_or_final_version / abstract / toc / Chemistry / Master / Master of Philosophy

The electron density of an ion is strongly influenced by its environment in a condensed phase. When the environment changes, for example due to thermal motion, non-trivial changes in the electron density, and hence the interionic interactions occur. These interactions give rise to many-body effects in the potential. In order to represent this phenomenon in molecular dynamics (MD) simulations a method has been developed in which the environmentally-induced changes in the ionic properties are represented by extra dynamical variables. These extra variables are handled in an extended Lagrangian formalism by techniques analogous to those used in Car and Parrinello's ab initio MD method. At its simplest level (the polarizable-ion model or PIM) induced dipoles are represented. With the PIM it has proven possible to quantitatively account for numerous properties of divalent metal halides, which had previously been attributed to unspecific "covalent" effects. In the solid-state the prevalence of layered crystal structures is explained. Analogous non-coulombic features in liquid structures, in particular network formation in "strong" liquids like ZnCl₂ , have been studied as has network disruption by "modifiers" like RbCl. This work leads to an understanding of the relationship between the microscopic structure and anomalous peaks ("prepeaks") seen in diffraction data of such materials. The PIM was extended to include induced quadrupoles and their effect studied in simulations of AgCl. In the solid-state it is found that the both are crucial in improving the phonon dispersion curves with respect to experiment. In the liquidstate polarization effects lower the melting point markedly. For oxides the short-range energy has been further partitioned into overlap and rearrangement energies and electronic structure calculations are used to parameterize a model in which the radius of the anion is included as an additional degree of freedom. The Bl → B2 phase transition is studied in MgO and CaO and the differences between the new model and a rigid-ion model are analysed.

Polymer nanocomposites (PNCs) have found their way into our everyday lives in a long list of applications, including airplane parts and car tires. This is due to their unique properties of combining the strengths of their constituents – elasticity and stiffness – while mitigating their weaknesses – softness and brittleness. In the past few decades, they have generated more interest due to the discovery that the PNCs’ optical, electrical, and a host of other properties can be tuned for specific use by controlling the assembly and dispersion of nanoparticles (NPs) within the host polymer matrix. The grafting of some of the matrix chains onto the surface of the NPs not only improves NP miscibility but also grants an additional handle tocontrol the self-assembly of NPs. However, at present, there remains many open questions in the field of these novel PNCs. For instance, it is commonly believed that long enough matrix polymers of length P will spontaneously dewet a chemically identical polymer layer, comprised of sufficient chains of length N , end-grafted to a flat surface (”brush”). This entropically driven idea is frequently used to explain experiments in which 10-20 nm diameter polymer-grafted NPs are observed to phase separate from homopolymer matrices for P/N⪆4. At lower grafting densities, these entropic effects are also thought to underpin the self-assembly of grafted NPs into a diverse set of structures. To explore the validity of this picture, a two-pronged approach is used in this thesis, exploring such systems from both a single NP and a multi-NP point of view in order to find novel methods for understanding and controlling NP dispersion in polymers. In each of the chapters, we employ coarse-grained Molecular Dynamics (MD) simulations to understand the self-assembly and dispersion behavior in PNCs, with the experimental analog being primarily polystyrene (PS) grafted silica NPs in PS matrices. We start by investigating the entropic effects of P/N on the brush of a single grafted NP, taking advantage of an indirect umbrella sampling method (INDUS) to quantify matrix density fluctuations. This method essentially makes use of an external biasing potential to mimic the dewetting of the brush. We find for the first time that entropic P/N effects can be identified at the single NP level and is primarily surface driven. INDUS is later extended to two-body and many-body NP systems, to understand the role of NP surfactantcy in the self-assembly of grafted NPs and create free-energy profiles for a range of inter-NP separations. Finally, results from a comprehensive series of large-scale multi-NP simulations, where we consider NPs in the ≈ 5nm and ≈ 10nm size range. For the smaller NPs, we find no evidence of phase separation even for P/N = 10 in the absence of attractions. Instead, we discover that we are able to recreate most of the experimentally observed structures when allthe polymer chain monomers are equally attractive to each other but repel the NPs. Only when the NPs are in the ≈ 10nm size range that we are able to access the phase separated morphologies. Our results thus imply that experimental situations where the grafting density is low are dominated by the surfactancy of the NPs, which is driven by the chemical mismatch between the inorganic core and the organic ligands (the graft and free chains are chemically identical). Entropic effects, i.e. the translational entropy of the NPs and the matrix, the entropy of mixing of the grafts and the matrix, and the conformational entropy of the chains appear to thus play a second order effect even in the context of these model systems. Each of these insights provides details around controlling the organization and assembly of NPs in polymers for the purpose of improving their mechanical properties, all while changing the way in which the material is designed.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Nuclear Engineering, 1982. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Bibliography: leaves 144-147. / by Benito De Celis. / Ph.D.

Amyloids are highly ordered cross-β sheet aggregates that are associated with many diseases such as Alzheimer‟s, type II diabetes and prion diseases. Recently a progress has been made in structure elucidation, environmental effects and thermodynamic properties of amyloid aggregates. However, detailed understanding of how mutation, packing polymorphism and small organic molecules influence amyloid structure and dynamics is still lacking. Atomistic modeling of these phenomena with molecular dynamics (MD) simulations holds a great promise to bridge this gap. This Thesis describes the results of MD simulations, which provide insight into the effects of mutation, packing polymorphism and molecular inhibitors on amyloid peptides aggregation. Chapter 1 discusses the structure of amyloid peptides, diseases associated with amyloid aggregation, mechanism of aggregation and strategies to treat amyloid diseases. Chapter 2 describes the basic principles of molecular dynamic simulation and methods of trajectory analysis used in the Thesis. Chapter 3 presents the results of the study of several all-atom molecular dynamics simulations with explicit solvent, starting from the crystalline fragments of two to ten monomers each. Three different hexapeptides and their analogs produced with single glycine replacement were investigated to study the structural stability, aggregation behavior and thermodynamics of the amyloid oligomers. Chapter 4 presents multiple molecular dynamics (MD) simulation of a pair polymorphic form of five short segments of amyloid peptide. Chapter 5 describes MD study of single-layer oligomers of the full-length insulin with a goal to identify the structural elements that are important for insulin amyloid stability, and to suggest single glycine mutants that may improve formulation. Chapter 6 presents the investigation of the mechanism of the interaction of polyphenols molecules with the protofibrils formed by an amyloidogenic hexapeptide fragment (VQIVYK) of Tau peptide by molecular dynamics iii simulations in explicit solvent. We analyzed the trajectories of the large (7×4) aggregate with and without the polyphenols. Our MD simulations for both the short and full length amyloids revealed adding strands enhances the internal stability of wildtype aggregates. The degree of structural similarity between the oligomers in simulation and the fibril models constructed based on experimental data may explain why adding oligomers shortens the experimentally observed nucleation lag phase of amyloid aggregation. The MM-PBSA free energy calculation revealed nonpolar components of the free energy is more favorable while electrostatic solvation is unfavorable for the sheet to sheet interaction. This explains the acceleration of aggregation by adding nonpolar co-solvents (methanol, trifluoroethanol, and hexafluoroisopropanol). Free energy decomposition shows residues situated at the interface were found to make favorable contribution to the peptide -peptide association. The results from the simulations might provide both the valuable insight for amyloid aggregation as well as assist in inhibitor design efforts. First, the simulation of the single glycine mutants at the steric zipper of the short segments of various pathological peptides indicates the intersheet steric zipper is important for amyloid stability. Mutation of the side chains at the dry steric zipper disrupts the sheet to sheet packing, making the aggregation unstable. Thus, designing new peptidomimetic inhibitors able to prevent the fibril formation based on the steric zipper motif of the oligomers, similar to the ones examined in this study may become a viable therapeutic strategy. The various steric zipper microcrystal structures of short amyloid segments could be used as a template to design aggregation inhibitor that can block growth of the aggregates. Modification of the steric zipper structure (structure based design) with a single amino acid changes, shuffling the sequences, N- methylation of peptide amide bonds to suppress hydrogen iv bonding ability of NH groups or replacement with D amino acid sequence that interact with the parent steric zipper could be used in computational search for the new inhibitors. Second, the polyphenols were found to interact with performed oligomer through hydrogen bonding and induce conformational change creating an altered aggregate. The conformational change disrupts the intermolecular amyloid contact remodeling the amyloid aggregate. The recently reported microcrystal structure of short segments of amyloid peptides with small organic molecules could serve as a pharamcophore for virtual screening of aggregation inhibitor using combined docking and MD simulation with possible enhancement of lead enrichment. Finally, our MD simulation of short segments of amyloids with steric zipper polymorphism showed the stability depends on both sequence and packing arrangements. The hydrophilic polar GNNQQNY and NNQNTF with interface containing large polar and/or aromatic side chains (Q/N) are more stable than steric zipper interfaces made of small or hydrophobic residues (SSTNVG, VQIVYK, and MVGGVV). The larger sheet to sheet interface of the dry steric zipper through polar Q/N rich side chains was found to holds the sheets together better than non Q/N rich short amyloid segments. The packing polymorphism could influence the structure based design of aggregation inhibitor and a combination of different aggregation inhibitors might be required to bind to various morphologic forms of the amyloid peptides.

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Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Nuclear Engineering, 1982. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Includes bibliographical references. / by Francisco Javier Carrion. / M.S.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Nuclear Engineering, 1982. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Includes bibliographical references. / by Khaled Awni Touqan. / Ph.D.

Proteins and DNA are essential to life as we know it and understanding their function is understanding their structure and dynamics. The importance of the latter is being appreciated more in recent years and has led to the development of novel interdisciplinary techniques and approaches to studying protein function. Three techniques to study protein structure and dynamics have been used and combined in different ways in the context of this thesis and have led to a better understanding of the three systems described herein. X-ray crystallography is the oldest and still arguably most popular technique to study macromolecular structures. Nuclear magnetic resonance (NMR) spectroscopy is a not much younger technique that is a powerful tool not only to probe molecular structure but also dynamics. The last technique described herein are molecular dynamics (MD) simulations, which are only just growing out of their infancy. MD simulations are computer simulations of macromolecules based on structures solved by X-ray crystallography or NMR spectroscopy, that can give mechanistic insight into dynamic processes of macromolecules whose amplitudes can be estimated by the former two techniques. MD simulations of the model protein GB3 (B3 immunoglobulin-binding domain of streptococcal protein G) were conducted to identify origins of discrepancies between order parameters derived from different sets of MD simulations and NMR relaxation experiments.The results highlight the importance of time scales as well as sampling when comparing MD simulations to NMR experiments. Discrepancies are seen for unstructured regions like loops and termini and often correspond to nanosecond time scale transitions between conformational substates that are either over- or undersampled in simulation. Sampling biases can be somewhat remedied by running longer (microsecond time scale) simulations. However, some discrepancies persist over even very long trajectories. We show that these discrepancies can be due to the choice of the starting structure and more specifically even differences in protonation procedures. A test for convergence on the nanosecond time scale is shown to be able to correct for many of the observed discrepancies. Next, MD simulations were used to predict in vitro thermostability of members of the bacterial Ribonuclease HI (RNase H) family of endonucleases. Thermodynamic stability is a central requirement for protein function and a goal of protein engineering is improvement of stability, particularly for applications in biotechnology. The temperature dependence of the generalized order parameter, S, for four RNase H homologs, from psychrotrophic, mesophilic and thermophilic organisms, is highly correlated with experimentally determined melting temperatures and with calculated free energies of folding at the midpoint temperature of the simulations. This study provides an approach for in silico mutational screens to improve thermostability of biologically and industrially relevant enzymes. Lastly, we used a combination of X-ray crystallography, NMR spectroscopy and MD simulations to study specificity of the interaction between Drosophila Hox proteins and their DNA target sites. Hox proteins are transcription factors specifying segment identity during embryogenesis of bilaterian animals. The DNA binding homeodomains have been shown to confer specificity to the different Hox paralogs, while being very similar in sequence and structure. Our results underline earlier findings about the importance of the N-terminal arm and linker region of Hox homeodomains, the cofactor Exd, as well as DNA shape, for specificity. A comparison of predicted DNA shapes based on sequence alone with the shapes observed for different DNA target sequences in four crystal structures when in complex with the Drosophila Hox protein AbdB and the cofactor Exd, shows that a combined ”induced fit”/”conformational selection” mechanism is the most likely mechanism by which Hox homeodomains recognize DNA shape and achieve specificity. The minor groove widths for all sequences is close to identical for all ternary complexes found in the different crystal structures, whereas predicted shapes vary between the different DNA sequences. The sequences that have shown higher affinity to AbdB in vitro have a predicted DNA shape that matches the observed DNA shape in the ternary complexes more closely than the sequences that show low in vitro affinity to AbdB. This strongly suggests that the AbdB-Exd complex selects DNA sequences with a higher propensity to adopt the final shape in their unbound form, leading to higher affinity. An additional AbdB monomer binding site with a strongly preformed binding competent shape is observed for one of the oligomers in the reverse complement strand of one of the canonical (weak) Hox-Exd complex binding site. The shape preference seems strong enough for AbdB monomer binding to compete with AbdB-Exd dimer binding to that same oligomer, suggested by the presence of both binding modes in the same crystal. The monomer binding site is essentially able to compete with the dimer binding site, even though binding with the cofactor is not possible, because its shape is very close to the ideal shape. A comparison of different crystal structures solved herein and in the literature as well as a set of molecular dynamics simulations was performed and led to insights about the importance of residues in the Hox N-terminal arm for the preference of certain Hox paralogs to certain DNA shapes. Taken together all these insights contribute to our understanding of Hox specificity in particular as well as protein-DNA interactions in general.