Andrews Casey T, Elcock Adrian H
Department of Biochemistry, University of Iowa, Iowa City, IA 52242.
J Chem Theory Comput. 2013 Oct 8;9(10). doi: 10.1021/ct400371h.
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 in order 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 sidechains, fewer differences are observed between the force fields, but significant differences are again observed for aromatic interactions of phenylalanine sidechains. 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.
虽然现在人们普遍认为，生物细胞内高度拥挤的环境有可能显著改变生物分子的热力学性质，但对于盐桥和疏水相互作用等基本类型的相互作用的热力学在高生物分子浓度下会增强或减弱到何种程度，目前尚不清楚。作为解决这个问题的一种方法，我们进行了一系列全原子显式溶剂分子动力学（MD）模拟，以研究溶质浓度增加对四种两性离子氨基酸在水溶液中行为的影响。我们模拟了含有甘氨酸、缬氨酸、苯丙氨酸或天冬酰胺的系统，浓度分别为50、100、200和300mg/ml。每个分子系统都进行了1μs的模拟，以便获得热力学参数的统计收敛估计，并且每个系统都使用8种不同的力场和水模型进行模拟；总模拟时间为128μs。从模拟中计算出的四种氨基酸的密度、粘度和介电增量已与相应的实验测量值进行了比较。虽然所有的力场在再现密度增量方面表现良好，但粘度和介电增量的差异引发了关于模拟力场准确性以及某些情况下实验数据准确性的问题。我们还观察到各种力场对盐桥相互作用热力学的描述存在很大差异，令人惊讶的是，这些差异还导致了它们对溶质浓度依赖性的定性不同预测。对于缬氨酸侧链的脂肪族相互作用，力场之间观察到的差异较少，但对于苯丙氨酸侧链的芳香族相互作用，再次观察到显著差异。综合来看，这些结果突出了使用显式溶剂模拟方法来理解浓缩系统中行为的潜在能力，但也暗示了使用这些方法获得细胞内环境中行为的一致观点可能存在的潜在困难。
