Molecular Dynamics Simulations of Highly Crowded Amino Acid Solutions: Comparisons of Eight Different Force Field Combinations with Experiment and with Each Other
Molecular Dynamics Simulations of Highly Crowded Amino Acid Solutions: Comparisons of Eight Different Force Field Combinations with Experiment and with Each Other
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DOI：
10.1021/ct400371h
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发表时间：
2013-10-01
影响因子：
5.5
通讯作者：
Elcock, Adrian H.
中科院分区：
文献类型：
--
作者：
Andrews, Casey T.;Elcock, Adrian H.
尽管现在人们普遍认为生物细胞内的高度拥挤条件有可能显著改变生物分子的热力学性质，但高生物分子浓度在多大程度上加强或削弱了盐桥和疏水相互作用等基本类型相互作用的热力学尚不清楚。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，研究了增加溶质浓度对四种两性离子氨基酸在水溶液中行为的影响。我们模拟了甘氨酸、缬氨酸、苯丙氨酸或天冬氨酸的浓度分别为50、100、200和300毫克/毫升的体系。对每个分子体系进行1亩S模拟，得到热力学参数的统计收敛估计值，每个体系用8种不同的力场和水模型进行模拟；联合模拟时间为128亩S。将模拟得到的四种氨基酸的密度、粘度和介电增量与相应的实验值进行了比较。虽然所有的力场都很好地再现了密度增量，但粘度增量和介电增量的差异引发了对模拟力场的准确性以及在某些情况下对实验数据的质疑。我们还观察到不同力场对盐桥相互作用热力学的描述之间的巨大差异，令人惊讶的是，这些差异也导致了对它们对溶质浓度依赖性的定性不同的预测。对于缬氨酸侧链的脂肪族相互作用，力场之间的差异较小，但对于苯丙氨酸侧链的芳香族相互作用，则再次观察到显著的差异。综上所述，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的行为的潜在力量，但也暗示了使用这些方法来获得细胞内环境中的行为的一致视图的潜在困难。
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 mu s 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 mu s. 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.