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.

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We employ molecular dynamics simulations to investigate the evaporation process of nanosized droplets adsorbed on a substrate. Beads interacting with each other via Lennard-Jones (LJ) potentials are used to construct the simulation systems. The solid substrate contains 6 layers of beads forming a face-centered-cubic lattice. The bottom 3 layers are held rigid while the rest is kept at a constant temperature with a Langevin thermostat. A liquid droplet, consisting of LJ beads as well, is placed on top of the substrate. An appropriate amount of vapor beads are also supplied to the simulation box to help establish liquid-vapor equilibrium. To ensure adsorption, a stronger attraction is rendered between the droplet and a circular patch of 3 layers of beads at the center of the substrate surface while the rest of the substrate is made non-sticky for the fluid beads. During equilibration, the droplet and vapor are maintained at the same temperature as the thermalized substrate. After relaxation, the droplet adheres to the attractive patch as expected. Then a deletion zone is introduced into the top part of the vapor region. Fluid beads in this zone are removed at a given rate. To ensure that the evaporation dynamics and kinetics are properly captured, only the thermalized substrate is kept at the constant temperature during droplet evaporation. To carry out steady-state evaporation, the removed beads are reintroduced into a channel through the substrate and right below the droplet's center. These beads are then supplied to the droplet, compensating for the evaporation loss at the droplet surface. When the evaporation rate and the insertion rate are balanced, the system enters a steady state with the droplet undergoing continuous evaporation and its contact line pinned at the boundary of the attractive patch on the substrate. A one-to-one correspondence is found between the evaporation rate and the total number of fluid beads in the simulation box, as well as the contact angle of the droplet. Using this steady nonequilibrium system, we have mapped out the flow, temperature, and density fields inside and around the evaporating droplet as well as the local evaporation flux along the droplet surface with unprecedented resolutions. The results are used to test the existing theories on sessile droplet evaporation. / Master of Science / Droplet evaporation is a widespread natural phenomenon with numerous applications across various fields. While there has been extensive research on droplet evaporation, it remains a challenge to characterize the interior of the droplet and the local evaporation behavior on the droplet surface. Here we employ molecular dynamics (MD) simulation to model a nanosized droplet adsorbed on a substrate, which evaporates continuously while maintains a constant shape. This is realized by supplying the evaporated fluid back to the bottom of the droplet through an in-silico approach. Such a steady-evaporation system allows us to accurately map out the internal capillary flow of the evaporating droplet with a pinned contact line, where the droplet, vapor, and substrate meet. We find that local evaporation occurs faster near the contact line than at the apex of the droplet.

Catamarans provide vast deck space, high thrust efficiency, and excellent transverse stability, however, in rough conditions they can be susceptible to deck slamming from head seas or bow diving in following seas and a pitch-roll coupling effect that can lead to uncomfortable corkscrew motion under bow-quartering seas. A new class of catamaran called Wave-Adaptive Modular Vessels (WAM-V™) aims to help mitigate oceanic input from the cabin by allowing for the relative motion of components not common to classic catamaran design. This thesis presents a set of multi-body dynamics simulation models created for two active WAM-Vs™ along with analysis on their suspension characteristics. Both models provide conclusive and realistic results, with the final model being validated against on-water testing data from a 12-ft unmanned prototype WAM-V. The first of these simulations serves primarily as a tool to evaluate WAM-V™ response characteristics with respect to a variety of parametric variations. The modeling environment is highlighted along with details of the parametric simulation and how it was created. The results fall in line with our expectations and are presented along with analysis of the sensitivity of each parameter at three longitudinal locations. The final simulation attempts to model the response of a 12-ft unmanned surface vessel (USV) prototype of the WAM-V™ configuration. Testing data is collected, processed, and applied to the model for validation of its prediction accuracy. The results of the sea tests indicate that the simulation model performs well in predicting USV motions at sea. Future considerations for testing WAM-Vs™ can include changes in suspension and mass parameters as well as limiting particular degrees-of-freedom by making their joints rigid. / Master of Science

Gauge invariant shielding constants calculations of ?H, ?C, and ??N were calculated for acetonitrile in the gas and liquid phases. Dierent basis sets as well as dierent ab initio and DFT methods were tested to select a time-ecient level of theory with reasonable accuracy. The eect of nuclear motion on the shielding constants was also explored. To investigate solvent eects on the shielding constants of acetonitrile, dierent clusters were extracted from molecular dynamics simulations. Convergence to the experimental values varied for the dierent clusters. The geometry of the central molecule in a cluster played an important factor in reaching convergence. / Master of Science

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.