Computer simulation and theory of amino acid interactions in solution

Abstract

The force fields used in computer simulations play an important role in describing a particular system. In order to estimate the accuracy of a force field, physical or thermodynamic properties are usually compared with simulation results. Recently, we have been developing a force field which is called the Kirkwood-Buff Force Field (KBFF). This force field is established by transforming experimental data into Kirkwood-Buff (KB) integrals and then attempting to reproduce those KBIs with molecular dynamic (MD) simulations. Here we investigate a variety of intermolecular interactions in aqueous solutions through KB theory and molecular simulations. First, we describe a force field for the simulation of alkali halide aqueous solutions. These models are developed specifically to reproduce the experimentally determined Kirkwood-Buff integrals and solution activities as a function of molality. Additionally, other experimentally known properties including ion diffusion constants, relative permittivities, the densities and heats of mixing are reproduced by these models. Second, In an effort to understand the interactions which occur between amino acids in solution we have developed new force fields for simple amino acids and their analogs including glycine, betaine, β-alanine, dl-alanine, NH4Cl, NH4Br, N(CH3)4Cl, N(CH3)4Br, CH3NH3Cl, and CH3COONa. The new force fields reproduce the experimental Kirkwood-Buff integrals which describe the relative distribution of all the species in a solution mixture. Furthermore, it is shown that these simple amino acids can be understood in terms of the interactions of their functional groups and that, to a very good approximation, the transferability and additivity usually assumed in the development of biomolecular force fields appear to hold true. Third, an analysis of the effect of a cosolvent on the association of a solute in solution is presented by using the Kirkwood-Buff theory of solutions. The derived expressions provide a foundation for the investigation of cosolvent effects on molecular and biomolecular equilibria, including protein association, aggregation, and cellular crowding. Finally, in an effort to understand peptide aggregation at the atomic level we have performed simulations of polyglycine ((gly)n) using our recently developed force fields. Experimentally, the association of glycine polypeptides increases with n. Our force fields reproduce this behavior, and we investigated the reasons behind this trend. In addition to studying closed ensembles, we also simulate these systems in a semi-open ensemble that was designed to mimic cellular environments typically open to water, using a simple direct approach. The differences between the two ensembles are investigated and compared with our recent theoretical descriptions of aggregating systems using Kirkwood-Buff theory.