Molecular dynamics simulations of highly crowded amino acid solutions: Comparisons of eight different force field combinations with experiment and with each other

Abstract

Although it is now commonly accepted that the highly crowded conditions encountered inside biological cells have the potential to significantly alter the thermodynamic properties of biomolecules, it is not known to what extent the thermodynamics of fundamental types of interactions such as salt bridges and hydrophobic interactions are strengthened or weakened by high biomolecular concentrations. As one way of addressing this question we have performed a series of all-atom explicit solvent molecular dynamics (MD) simulations to investigate the effect of increasing solute concentration on the behavior of four types of zwitterionic amino acids in aqueous solution. We have simulated systems containing glycine, valine, phenylalanine, or asparagine at concentrations of 50, 100, 200, and 300 mg/mL. Each molecular system has been simulated for 1 μs to obtain statistically converged estimates of thermodynamic parameters, and each has been conducted with 8 different force fields and water models; the combined simulation time is 128 μs. The density, viscosity, and dielectric increments of the four amino acids calculated from the simulations have been compared to corresponding experimental measurements. While all of the force fields perform well at reproducing the density increments, discrepancies for the viscosity and dielectric increments raise questions both about the accuracy of the simulation force fields and, in certain cases, the experimental data. We also observe large differences between the various force fields' descriptions of the interaction thermodynamics of salt bridges and, surprisingly, these differences also lead to qualitatively different predictions of their dependences on solute concentration. For the aliphatic interactions of valine side chains, fewer differences are observed between the force fields, but significant differences are again observed for aromatic interactions of phenylalanine side chains. Taken together, the results highlight the potential power of using explicit-solvent simulation methods to understand behavior in concentrated systems but also hint at potential difficulties in using these methods to obtain consistent views of behavior in intracellular environments. © 2013 American Chemical Society.