Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)

Legacy Department



Dr. Steven J. Stuart

Committee Member

Dr. Robert A. Latour

Committee Member

Dr. Brian N. Dominy

Committee Member

Dr. Jason D. McNeill


Molecular dynamics (MD) simulations were carried out for aqueous dipeptides, water over self-assembled monolayer (SAM) surfaces, and the nicotinic acetylcholine receptor (nAChR) ion channel. The main goal is to use advanced methods to increase the accuracy of molecular dynamics simulations while seeking solutions to problems relevant to chemistry, biophysics and materials science. In addition, activation energies of several cyclodimerization reactions were studied quantum mechanically. The simulations of the aqueous dipeptides and SAM surfaces involve modeling and detailed analysis of interfacial water, which is of interest to a range of fields from biology to materials science. For example, water has a central role in biology and medicine since biomolecules cannot function without water. Both sets of simulations were performed using both polarizable and nonpolarizable force fields. These systems were used as a test ground to assess the effects of explicit incorporation of polarizability and also to determine whether the models can adequately reproduce the experimental data, in particular, the aggregation data of aqueous dipeptides and contact angles of water over SAMs of different chemical character. Since the systems are well-characterized and relatively simple, they provide excellent models to test polarizable force fields to increase the accuracy of molecular dynamics simulations. Polarizable water was depolarized around dipeptide solutes and also at the interface with different SAM surfaces, reflecting its ability to adapt to heterogeneous electrostatic environments. Although the water shows more realistic structure and dynamics in the polarizable simulations, the peptide aggregation behavior agrees less well with the experiment. In this case, neither model successfully reproduces the experimental degree of aggregation. In the case of SAM surfaces, both sets of simulations produce fairly similar results. More studies are suggested to further test and improve the polarizable force fields. The third system studied is the modeling of wild-type and mutant nAChR ion channel proteins. Adaptive biasing force method was used to achieve improved sampling, and subsequently increase the efficiency and accuracy of MD simulations. The nAChR channels are involved in a number of cognitive and brain functions including learning and memory. Dysfunction in these receptors are associated in a variety of neuronal diseases including epilepsy, schizophrenia and Alzheimer's Disease. The present study models the wild-type and two physiologically-relevant mutant structures to assess the effects of mutations on ion translocation energetics and the geometry of the channel. Open channel (conducting, active) structures were obtained from the available closed channel structure. One of the mutants was found to increase the energetic barrier for ion translocation, while the other one decreased the barrier. The ion channel structures were analyzed in detail to understand the structural changes that took place during the channel opening. The channel opening was found to be mediated by large-scale helix motions rather than small-scale side chain motions. Aside from the MD simulations, the final project involves quantum mechanical simulations, which are often needed in parametrization of molecular dynamics force fields. Density functional theory (DFT) calculations were employed to calculate the activation energies of three cyclodimerization reactions of trifluorovinyl ether monomers. The results agree with and further explain the experimentally observed reactivity in these types of reactions.

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