Reparametrization of Protein Force Field Nonbonded Interactions Guided by Osmotic Coefficient Measurements from Molecular Dynamics Simulations

There is a small,
but growing, body of literature describing the
use of osmotic coefficient measurements to validate and reparametrize
simulation force fields. Here we have investigated the ability of
five very commonly used force field and water model combinations to
reproduce the osmotic coefficients of seven neutral amino acids and
five small molecules. The force fields tested include AMBER ff99SB-ILDN,
CHARMM36, GROMOS54a7, and OPLS-AA, with the first of these tested
in conjunction with the TIP3P and TIP4P-Ew water models. In general,
for both the amino acids and the small molecules, the tested force
fields produce computed osmotic coefficients that are lower than experiment;
this is indicative of excessively favorable solute–solute interactions.
The sole exception to this general trend is provided by GROMOS54a7
when applied to amino acids: in this case, the computed osmotic coefficients
are consistently too high. Importantly, we show that all of the force
fields tested can be made to accurately reproduce the experimental
osmotic coefficients of the amino acids when minor modifications–some
previously reported by others and some that are new to this study–are
made to the van der Waals interactions of the charged terminal groups.
Special care is required, however, when simulating Proline with a
number of the force fields, and a hydroxyl-group specific modification
is required in order to correct Serine and Threonine when simulated
with AMBER ff99SB-ILDN. Interestingly, an alternative parametrization
of the van der Waals interactions in the latter force field, proposed
by the Nerenberg and Head-Gordon groups, is shown to immediately produce
osmotic coefficients that are in excellent agreement with experiment.
Overall, this study reinforces the idea that osmotic coefficient measurements
can be used to identify general shortcomings in commonly used force
fields’ descriptions of solute–solute interactions and
further demonstrates that modifications to van der Waals parameters
provide a simple route to optimizing agreement with experiment.

目前已有少量但逐年增长的文献，阐述了利用渗透系数（osmotic coefficient）测量来验证与重新参数化模拟力场（force field）的研究路径。本研究针对五种极为常用的力场与水模型组合，探究其重现七种中性氨基酸（neutral amino acids）及五种小分子（small molecules）渗透系数的能力。本次测试的力场包括AMBER ff99SB-ILDN、CHARMM36、GROMOS54a7以及OPLS-AA，其中第一种力场分别与TIP3P、TIP4P-Ew水模型联用进行测试。总体而言，无论针对氨基酸还是小分子，本次测试的力场所计算得到的渗透系数均低于实验值，这表明溶质-溶质相互作用过于有利。唯一偏离该整体趋势的情况是GROMOS54a7应用于氨基酸时的结果：此时计算得到的渗透系数始终偏高。值得注意的是，我们证实，若对带电端基的范德华相互作用（van der Waals interactions）进行小幅修改——部分修改已被此前其他研究报道，部分为本研究首次提出——所有测试力场均可准确重现氨基酸的实验渗透系数。不过，使用多款力场模拟脯氨酸（Proline）时需格外谨慎；而当使用AMBER ff99SB-ILDN模拟丝氨酸（Serine）与苏氨酸（Threonine）时，需针对羟基基团进行特定修改以修正结果。有趣的是，由Nerenberg与Head-Gordon团队提出的针对该力场的范德华相互作用替代参数化方案，可直接生成与实验结果高度吻合的渗透系数。综上，本研究进一步证实，渗透系数测量可用于识别常用力场在溶质-溶质相互作用描述上的普遍缺陷，并验证了修改范德华参数是优化力场与实验结果契合度的简便途径。