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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.

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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.

No / There is considerable interest, both fundamental and technological, in understanding how additives and impurities influence nucleation, and in being able to modulate nucleation in a predictable way using designer auxiliary molecules. Notable applications involving auxiliaries include the control of nucleation in proteins, inhibition of urinary stone formation, inhibition of ice formation in living tissues during cryoprotection, prevention of blockages in oil and gas pipelines due to wax precipitation, and gas hydrate formation. Despite the immense interest, our understanding of how these molecules exert their effect is still rudimentary, partially because the molecular level processes involved are inaccessible to experiment. We have investigated mechanisms of action of nucleation additives and have derived explicit rules for designing additive molecules for modulating crystal nucleation. The mechanisms of action and the design features have been derived using molecular simulation of simple model systems. Our studies reveal that an effective nucleation inhibitor should have a strong interaction with the solute and have a structure that is able to disrupt the periodicity characterizing the emerging nucleus. Disruption can be achieved by steric effects resulting from structural differences between the additive and solute molecules, the additive possessing extensive degrees of freedom, or via a strong energetic interaction with the solute. Additive molecules that have an amphiphilic character and end up at the solute/solvent interface can inhibit, retard or promote nucleation depending on their specific structure and interactions with the solute and solvent and the given supersaturation, and these specific features and the link with the supersaturation will be discussed. These findings will help to rationalize the mechanisms of action of known nucleation inhibitors and modulators. They will also serve as a framework for rationally identifying or designing additive molecules for either inhibiting or promoting nucleation in specific systems.

No / To gain a better understanding of how ethanol affects biological membranes, we have performed a series of atomic-scale molecular dynamics simulations of phospholipid membranes in aqueous solution with ethanol, whose concentration was varied from 2.5 to 30 mol % (lipid-free basis). At concentrations below the threshold value of ~12 mol % (30.5 v/v %) ethanol induces expansion of the membrane, accompanied by a drop in the membrane thickness as well as disordering and enhanced interdigitation of lipid acyl chains. These changes become more pronounced with increase in ethanol concentration, but the bilayer structure of the membrane is maintained. Above the threshold concentration the appearance of multiple transient defects in the lipid/water interface eventually gives rise to desorption and assembly of some of the lipids into non-bilayer structures within the membrane interior. These structures, being small and irregular, resemble inverted micelles and have a long-lived character. Furthermore, formation of the non-bilayer structures is accompanied by mixing of lipids that belong to the opposite membrane leaflets, thereby leading to irreversible changes in the membrane structure. Remarkably, this observation of the formation of non-bilayer structures within the membrane interior, being in good agreement with experimental data, is found to be robust with respect to both the simulation conditions (the system size and the presence of salt) and the type of lipids (phosphatidylcholine and phosphatidylethanolamine). We discuss the significance of these non-bilayer structures in relation with the well-known ability of ethanol to promote membrane hemifusion as well as with the possible role of the micelle-like structures as a delivery system for polar solutes and ions. The ethanol-induced "damage" to the bilayer structure also suggests that strong alcoholic beverages (~40 v/v %) might be potentially hazardous to the epithelial tissues of the human body (such as lips, mouth, throat, gullet, and stomach) that come in direct contact with high-concentrations of ethanol.