Molecular dynamics (MD) provides an atomically detailed description of the dynamics of a system of atoms. It is a useful tool to understand how protein function arises from the dynamics of the atoms of the protein and of its environment. When the MD model is accurate, analyzing a MD trajectory unveils features of the proteins that are not available from a single snapshot or a static structure. When the sampling of the accessible configurations is accurate, we can employ statistical mechanics (SM) to connect the trajectory generated by MD to experimentally measurable kinetic and thermodynamic quantities that are related to function. In this dissertation I describe three applications of MD and SM in the field of biochemistry. First, I discuss the theory of alchemical methods to compute free energy differences. In these methods a fragment of a system is computationally modified by removing its interactions with the environment and creating the interactions of the environment with the new species. This theory provides a numerical scheme to efficiently compute protein-ligand affinity, solvation free energies, and the effect of mutations on protein structure. I investigated the theory and stability of the numerical algorithm. The second research topic that I discuss considers a model of the dynamics of a set of coarse variables. The dynamics in coarse space is modeled by the Smoluchowski equation. To employ this description it is necessary to have the correct potential of mean force and diffusion tensor in the space of coarse variables. I describe a new method that I developed to extract the diffusion tensor from a MD simulation. Finally, I employed MD simulations to explain at a microscopic level the stereospecificity of the enzyme ketoreductase. To do so, I ran multiple simulations of the enzyme bound with the correct ligand and its enantiomer in a reactive configuration. The simulations showed that the enzyme retained the correct stereoisomer closer to the reactive configuration, and highlighted which interactions are responsible for the specificity. These weak physical interactions enhance binding with the correct ligand even prior to the steps of chemical modification. / text

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

Computer simulations provide a powerful tool for the investigation of liquid crystalline phases. In this thesis the ability of simulations to calculate accurately the values of material parameters of liquid crystal molecules is investigated. An all-atom force field for liquid crystal molecules is developed using first principles density functional theory calculations on small organic molecules, which encompass key structural features of a range of common liquid crystalline molecules. Molecular dynamics simulations of these 'fragment' molecules are carried out in the liquid phase to test the force field parameters by determining densities and heats of vapourisation. Good agreement is found between experimental values and those calculated from simulation. Equilibrium molecular dynamics (MD) calculations were then performed for the nematogen n-4-(trans-n-pentylcyclohexyl)benzonitrile (PCH5). These simulations were performed using a fully atomistic model for several temperatures. The MD trajectories were used to obtain densities, order parameters, and values for the rotational viscosity coefficient 71. Several methods of obtaining 71 were tested based on the director angular velocity correlation function, the director mean-squared displacement, and statistical mechanics methods based on the rotational diffusion model. Good agreement is obtained between experimental values of 71 and those found from simulation. Further MD simulations of PCH5 using a 216 molecule system and the force field derived in this thesis were carried out to calculate the flexoelectric coefficients e(_s) and e(_b) for PCH5. The temperature dependence of and was examined along with the separate contributions to e(_s)and e(_b)arising bom the electrostatic and van der Waals interactions. The calculated values of e(_s)and e(_b) are consistent with available experimental data. The van der Waals and electrostatic contributions are found to be of similar magnitude and opposite sign.

- Alicyclic diols can hydrogen bond in many different ways and yield most interesting structures. In this thesis, eight C2-symmetric diols 48-50, 78, 79 and 81-83 were synthesized and their crystal structures were determined. No less than seven of these show unusual solid state behaviour: 48 and 78 are inclusion hosts; 49, 50 and 78 form doubly-stranded hydrogen-bonded ladder structures, where there is a strong preference for each strand to be homochiral; 78, 81 and 82 undergo self-resolution during recrystallization; and 83 forms chirally pure crystals (but the material is still racemic). - One of the favourable supramolecular synthons for hydroxy compounds is the (O-H)6 cycle of hydrogen bonds. When this cycle is formed by a racemic compound, its enantiomers alternate down-up-down etc. around the cycle. No case of an (O-H)6 cycle involving chirally pure hydroxy compounds is known. These observations indicate a strong preference for the (O-H)6 cycle being constructed from achiral or racemic molecules rather than from chirally pure hydroxyl compounds. Racemic (??)-48 and (??)-92 which are already known to form (O-H)6 cycles in the solid state were prepared in chirally pure form and their X-ray crystal structures determined. No (O-H)6 cycles were observed for these homochiral diols. These findings confirm that the (O-H)6 motif occurs only for achiral or racemic compounds. - Similarly, the edge-to-edge eight-membered aryl C-H???N dimer involves either achiral molecules or those of opposite chirality. No chirally pure dimers of this type are reported. Racemic compounds 42-44 that are known to pack using the C-H???N dimer were synthesized in chirally pure form. No edge-to-edge eight-membered aryl C-H???N dimers were formed in the solid state. Hence this supramolecular synthon is only favoured for achiral or racemic compounds only. - Other major conclusions are that the cause of self-resolution is due to packing energy. In some cases it is likely that solvent choice, or solvent plus temperature selection, can be used to control self-resolution.

Thesis (Ph.D.)--University of Delaware, 2007. / Principal faculty advisor: Suresh G. Advani, Dept. of Mechanical Engineering. Includes bibliographical references.