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.

现有文献中虽为数不多，但已有部分研究论述了利用渗透系数测量方法来验证和重新参数化模拟力场。本研究旨在探讨五种极为常用的力场与水模型组合在重现七种中性氨基酸和五种小分子的渗透系数方面的能力。所测试的力场包括AMBER ff99SB-ILDN、CHARMM36、GROMOS54a7以及OPLS-AA，其中第一种力场与TIP3P和TIP4P-Ew水模型一同进行测试。总体而言，对于氨基酸和小分子，所测试的力场计算出的渗透系数均低于实验值；这表明了溶质-溶质相互作用过于有利。然而，GROMOS54a7在氨基酸中的应用却呈现出唯一的例外：在这种情况下，计算出的渗透系数始终过高。值得注意的是，我们表明，通过对带电端基团的范德华相互作用进行微小的修改——其中一些已被他人报道，而另一些则是本研究的新发现——所有测试的力场均能精确地重现氨基酸的实验渗透系数。然而，在模拟脯氨酸时，需要特别注意某些力场，并且当使用AMBER ff99SB-ILDN模拟丝氨酸和苏氨酸时，需要对羟基团进行特定的修改。有趣的是，Nerenberg和Head-Gordon小组提出的该后一力场中范德华相互作用的替代参数化，被证明能够立即产生与实验结果极为一致的渗透系数。总体而言，本研究强化了渗透系数测量可用于识别常用力场描述溶质-溶质相互作用中的普遍不足的观点，并进一步证明了调整范德华参数为优化与实验结果的一致性提供了一条简单途径。