In the field of biology, MD simulations are continuously used to investigate biological studies. A Molecular Dynamics (MD) system is defined by the position and momentum of particles and their interactions. The dynamics of a system can be evaluated by an N-body problem and the simulation is continued until the energy reaches equilibrium. Thus, solving the dynamics numerically and evaluating the interaction is computationally expensive even for a small number of particles in the system. We are focusing on long-ranged interactions, since the calculation time is O(N^2) for an N particle system. In this dissertation, we are proposing two research directions for the MD simulation. First, we design a new variation of Multigrid (MG) algorithm called Multi-level charge assignment (MCA) that requires O(N) time for accurate and efficient calculation of the electrostatic forces. We apply MCA and back interpolation based on the structure of molecules to enhance the accuracy of the simulation. Our second research utilizes reconfigurable models to achieve fast calculation time. We have been working on exploiting two reconfigurable models. We design FPGA-based MD simulator implementing MCA method for Xilinx Virtex-IV. It performs about 10 to 100 times faster than software implementation depending on the simulation accuracy desired. We also design fast and scalable Reconfigurable mesh (R-Mesh) algorithms for MD simulations. This work demonstrates that the large scale biological studies can be simulated in close to real time. The R-Mesh algorithms we design highlight the feasibility of these models to evaluate potentials with faster calculation times. Specifically, we develop R-Mesh algorithms for both Direct method and Multigrid method. The Direct method evaluates exact potentials and forces, but requires O(N^2) calculation time for evaluating electrostatic forces on a general purpose processor. The MG method adopts an interpolation technique to reduce calculation time to O(N) for a given accuracy. However, our R-Mesh algorithms require only O(N) or O(logN) time complexity for the Direct method on N linear R-Mesh and N¡¿N R-Mesh, respectively and O(r)+O(logM) time complexity for the Multigrid method on an X¡¿Y¡¿Z R-Mesh. r is N/M and M = X¡¿Y¡¿Z is the number of finest grid points.

We have used a molecular modeling of both random and blocky sequence hydrogel networks of poly(N-vinyl-2-pyrrolidone-co-2-hydroxyethyl methacrylate) (P(VP-co-HEMA)) with a composition of VP:HEMA = 37:13 to investigate the effect of the monomeric sequence and the water content on the equilibrium structures and the mechanical and transport properties by full-atomistic molecular dynamics (MD) simulations. The degree of randomness of the monomer sequence for the random and the blocky copolymers, were 1.170 and 0.104, respectively, and the degree of polymerization was fixed at 50. The equilibrated density of the hydrogel was found to be larger for the random sequence than for the blocky sequence at low water contents (< 40 wt %), but this density difference decreased with increasing water content. The pair correlation function analysis shows that VP is more hydrophilic than HEMA and that the random sequence hydrogel is solvated more than the blocky sequence hydrogel at low water content, which disappears with increasing water content. Correspondingly, the water structure is more disrupted by the random sequence hydrogel at low water content but eventually develops the expected bulk-water-like structure with increasing water content. From mechanical deformation simulations, the stress-strain analysis showed that the VP is found to relax more efficiently, especially in the blocky sequence, so that the blocky sequence hydrogel shows less stress levels compared to the random sequence hydrogel. As the water content increases, the stress level becomes identical for both sequences. The elastic moduli of the hydrogels calculated from the constant strain energy minimization show the same trend with the stress-strain analysis. Ascorbic acid and D-glucose were used to study the effect of the monomeric sequence on the diffusion of small guest molecules within the hydrogels. By analyzing the pair correlation functions, it was found that the guest molecule has greater accessibility to the VP units than to the HEMA units with both monomeric sequences due to its higher hydrophilicity compared to the HEMA units. The monomeric sequence effect on the P(VP-co-HEMA) hydrogel is clearly observed with 20 wt % water content, but the monomeric sequence effect is significantly reduced with 40 wt % water content and disappears with 80 wt % water content. This is because the hydrophilic guest molecules are more likely to be associated with water molecules than with the polymer network at the high water content. By analyzing the mean square displacement, the displacement of the guest molecules and the inner surface area, it is also found that the guest molecule is confined in the system at 20 wt % water content, resulting in highly anomalous subdiffusion. Therefore, the diffusion of the guest molecules is directly affected by their interaction with the monomer units, the monomeric sequence and the geometrical confinement in the hydrogel at a low water content, but the monomeric sequence effect and the restriction on the diffusion of the guest molecule are significantly decreased with increasing the water content. We also investigated the de-swelling mechanisms of the surface-grafted poly(N-isopropylacrylamide) (P(NIPAAm)) brushes containing 1300 water molecules at 275 K, 290 K, 320 K, 345 K, and 370 K. We clearly observed the de-swelling of the water molecules for P(NIPAAm) above the lower critical solution temperature (LCST) (~305 K). Below the LCST, we did not observe the de-swelling of water molecules. Using the upper critical solution temperature (UCST) systems (poly(acrylamide) brushes) for comparison purposes, we did not observe the de-swelling of water molecules at a given range of temperatures. By analyzing the pair correlation functions and the coordination numbers, the de-swelling of the water molecules occurred distinctly around the isopropyl group of the P(NIPAAm) brush above the LCST because C(NIPAAm) does not offer sufficient interaction with the water molecules via the hydrogen bonding type of secondary interaction. We also found that the contribution of the N(NIPAAm)-O(water) pair is quite small because of the steric hindrance of the isopropyl group. By analyzing the change in the hydrogen bonds, the hydrogen bonds between polar groups and water molecules in the P(NIPAAm) brushes weaken with increasing temperature, which leads to the de-swelling of the water molecules out of the brushes above the LCST. Below the LCST, the change in the hydrogen bonds is not significant. Again, the contribution of the NH(NIPAAm)-water pairs is insignificant; the total number of hydrogen bonds is ~20, indicating that the interaction between the NH group and the water molecules is not significant due to steric hindrances. Lastly, we observed that the total surface area of the P(NIPAAm) brushes that is accessible to water molecules is decreased by collapsing the brushes followed by the de-swelling of water molecules above the LCST.

The synthesis of four homologous anthraquinones (AQ I-IV) bearing increasing lengths of polyethylene glycol (PEG) side chains and their binding to AT- and GC-rich DNA hairpins are reported. The molecules were designed such that the cationic charge is at a constant position and the ethylene glycol units chosen to allow significant increases in size with minimal changes in hydrophobicity. The mode and affinity of binding were assessed using circular dichroism (CD), nuclear magnetic resonance (NMR), surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC). The binding affinity decreased as the AQ chain length increased along the series with both AT- and GC-rich DNA. ITC measurements showed that the thermodynamic parameters of AQ I-IV binding to DNA exhibited significant enthalpy-entropy compensation. The enthalpy became more favorable while the entropy became less favorable. The correlation between enthalpy and entropy may involve not only the side chains, but also changes in the binding of water and associated counterions and hydrogen bonding. The interactions of AQ I-IV with GC-rich DNA have been studied via molecular dynamics (MD) simulations. The geometry, conformation, interactions, and hydration of the complexes were examined. As the side chain lengthened, binding to DNA reduced the conformational space, resulting in an increase in unfavorable entropy. Increased localization of the PEG side chain in the DNA groove, indicating some interaction of the side chain with DNA, also contributed unfavorably to the entropy. The changes in free energy of binding due to entropic considerations (-3.9 to -6.3 kcal/mol) of AQ I-IV were significant. The kinetics of a homologous series of anthraquinone threading intercalators, AQT I-IV with calf thymus DNA was studied using the stopped-flow. The threading mechanisms of the anthraquinones binding to DNA showed sensitivity to their side chain length. Fitting of the kinetic data led to our proposal of a two step mechanism for binding of AQT I, bearing the shortest side chain, and a three step mechanism for binding of the three longer homologs. Binding involves formation of an externally bound anthraquinone-DNA complex, followed by intercalation of the anthraquinone for AQT I-IV, then isomerization to another complex with similar thermodynamic stability for AQT II-IV.

We apply a molecular dynamics (MD) simulation technique to complex molecules at interfaces. Partitioning of dendritic surfactants into clay gallery and Ab protein behavior near hydrated lipids are chosen for the purpose. Using a full atomistic model of dendritic surfactants, the confinement force profiles featuring oscillatory fashion at moderate layer separation of 10 to 25 Å were observed. Integration of the confinement forces led to free energy profiles, which, in turn, were used to determine the final morphology of the nanocomposite. From the free energy profiles, smaller and linear surfactants (G1 and G2L) are expected to intercalate into the clay comfortably, while larger surfactants (G2 and G3) are expected to form frustrated intercalated structures due to the location and depth of the free energy minima. This would agree with the previous observations. As primary steps to understand the Ab protein behavior under biological conditions, simulations of bulk water and hydrated lipids were performed and the results were compared with the literature. Hydrated lipids were simulated using a full atomistic model of lipids (dipalmitoylphosphatidylcholine) and water with a cvff force-field and it was found that structural properties such as the molecular head group area and membrane thickness were accurately produced with MD simulation. Systems of the protein Ab(1-42) in bulk water were simulated and some secondary structural change, with loss of part of the a-helical structure, occurred during the 1 ns of simulation time at 323K. The fragment Ab(31-42) with b-sheet conformation was also simulated in bulk water, and the extended b-sheet structure became a bent structure. Simulations of Ab(1- 42) or Ab(31-42) near lipid bilayers have been performed to investigate the structural property changes under biological conditions. The different nature of structural change was observed from the simulations of the protein or fragment in water and near lipid bilayers due to the different solvent environment. The protein has close contacts with the membrane surface. It was impossible to observe the conformational change to b-sheet and protein entrance into the lipid bilayer within 1 ns simulations.

In the beginning of this study, Molecular dynamics simulation is utilized to investigate the behavior of water molecules confined between two Au plates of (001) planes separated by gaps of 24.48, 16.32, 12.24, 11.22, and 10.20 . The simulation results indicate that the arrangements of the water molecules are dependent on the gap size. An inspection of the variation of the self-diffusion coefficients with the gap size suggests that the difference between the dynamic properties of the water molecules in the z-direction and the x-y plane decreases as the distance between the two Au plates increases. Moreover, we discuss the effects of different lattice structures, (100), (110) and (111)¡Aon the water molecules. The simulation results indicate that the arrangements of the water molecules are dependent on Au plate surface structures. The adsorption of the plate creates flat water layers in the proximity of each plate surface for (100) and (111) cases, but wave-like water layer for Au (110) plate. The absorbed water layer is the most close to plate surface for (110) lattice structure. Moreover, the self-diffusion coefficient in the z-direction for (110) case is the largest, meanwhile, the water molecules have a greater ability to diffuse in the x-y plane for (100) case. Finally¡Athe density distribution, velocity profile, and diffusion coefficients of the water film in a Couette flow are studied. Shear viscosity and its dependence on the shear rate of the water film are also examined in the present research. The diffusion of the whole film increases dramatically as the shear rate greater than a critical value. The shear viscosity decreases as the shear rate increases, especially for the water film with a small thickness, which implies the shear-thinning behavior for viscosity of the nanoconfined film. Moreover, increase in shear viscosity with a decrease in the film thickness can also be found in the present study.

This thesis proposes algorithms to construct various nanosystems such as nanotori, nanogear and nanojunctions based on graphite type structures, exploiting the observed pentagonal and heptagonal defects. These produced systems are then simulated to test for their thermal stability and for their electronic properties. A brief review of the methods used is also included.

A central goal of computational biophysics and biochemistry is to understand the behavior, interactions, and reactions of molecules, and to interpret and facilitate experimental design. The objective of this thesis research is to use the molecular modeling and simulation techniques to advance our understanding of principles in molecular structure properties, recognition and interaction at the atomic level. First, a physical molecular mechanics model is built to study the conformational properties of depsipeptide, which shows potential for engineered protein mimetics with controllable structure and function. We explore the possible kinase-substrate binding modes and the likelihood of an [alpha]-helix docking interaction within a kinase active site. Finally, efficient physical models based on a polarizable potential function are developed to describe the structural properties and calculate protein-ligand binding affinities accurately for both trypsin and matrix metalloproteinase. / text

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Unilateral, below-knee amputees have altered gait mechanics, which can significantly affect mobility. For example, amputees often have asymmetric leg loading as well as higher metabolic cost and an increased risk of falling compared to non-amputees. Below-knee amputees lose the functional use of the ankle muscles, which are critical in non-amputee walking for providing body support, forward propulsion and leg-swing initiation. The ankle muscles also regulate angular momentum in non-amputees, which is important for providing body stability and preventing falls. Thus, compensatory mechanisms in amputee walking are developed to accomplish the functional tasks normally provided by the ankle muscles. In Chapters 2 and 3, three-dimensional forward dynamics simulations of amputee and non-amputee walking were generated to identify compensatory mechanisms and their effects on joint loading and metabolic cost. Results showed that the prosthesis provided body support, but did not provide sufficient body propulsion or leg-swing initiation. As a result, compensations by the residual leg gluteus maximus, gluteus medius, and hamstrings were needed. The simulations also showed the intact leg tibio-femoral joint contact impulse was greater than the residual leg and that the vasti and hamstrings were the primary contributors to the joint impulse on both the intact and residual legs. The amputee simulation had higher metabolic cost than the non-amputee simulation, which was primarily due to prolonged muscle activity from the residual leg gluteus maximus, gluteus medius, hamstrings, vasti and intact leg vasti and ankle muscles. In Chapter 4, whole-body angular momentum in amputees and non-amputees was analyzed. Reduced residual leg propulsion resulted in a smaller range of sagittal plane angular momentum in the second half of the gait cycle. Thus, to conserve angular momentum, reduced braking was needed in the first half of the gait cycle. Decreased residual leg braking appears to be an important mechanism to regulate sagittal plane angular momentum in amputee walking, but was also associated with a greater range of angular momentum that may contribute to reduced stability in amputees. These studies have provided important insight into compensatory mechanisms in below-knee amputee walking and have the potential to guide rehabilitation methods to improve amputee mobility. / text