Evaluating the Performance of Water Models with Host–Guest Force Fields in Binding Enthalpy Calculations for Cucurbit[7]uril–Guest Systems

Computational prediction of thermodynamic
components with computational
methods has become increasingly routine in computer-aided drug design.
Although there has been significant recent effort and improvements
in the calculation of free energy, the prediction of enthalpy (and
entropy) remains underexplored. Furthermore, there has been relatively
little work reported so far that attempts to comparatively assess
how well different force fields and water models perform in conjunction
with each other. Here, we report a comprehensive assessment of force
fields and water models using host–guest systems that mimic
many features of protein–ligand systems. These systems are
computationally inexpensive, possibly because of their small size
compared to protein–ligand systems. We present absolute enthalpy
calculations using the multibox approach on a set of 25 cucurbit[7]­uril–guest
pairs. Eight water models were considered (TIP3P, TIP4P, TIP4P-Ew,
SPC, SPC/E, OPC, TIP5P, Bind3P), along with five force fields commonly
used in the literature (GAFFv1, GAFFv2, CGenFF, Parsley, and SwissParam).
We observe that host–guest binding enthalpies are strongly
sensitive to the selection of force field and water model. In terms
of water models, we find that TIP3P and its derivative Bind3P are
the best performing models for this particular host–guest system.
The performance is generally better for aliphatic compounds than for
aromatic ones, suggesting that aromaticity remains a difficult property
to include accurately in these simple force fields.

借助计算方法开展热力学组分的预测，如今在计算机辅助药物设计领域已愈发成为常规操作。尽管近年来自由能计算领域已取得显著进展并投入大量研究工作，但焓（及熵）的预测仍有待深入探索。此外，迄今鲜有公开报道的研究尝试系统性对比评估不同力场与水模型联合使用时的表现优劣。
本研究借助模拟蛋白质-配体体系诸多特征的主客体体系，对多种力场与水模型开展了全面评估。相较于蛋白质-配体体系，此类体系因分子尺寸更小，计算成本更低廉。本研究采用多盒子（multibox）方法，对25组葫芦[7]脲-客体分子对开展了绝对焓计算。本次研究共考量了8种水模型（TIP3P、TIP4P、TIP4P-Ew、SPC、SPC/E、OPC、TIP5P、Bind3P），以及5种文献中常用的力场（GAFFv1、GAFFv2、CGenFF、Parsley、SwissParam）。
研究结果显示，主客体结合焓对力场与水模型的选择具有极强的敏感性。就水模型而言，本研究发现TIP3P及其衍生模型Bind3P在该特定主客体体系中表现最优。总体而言，脂肪族化合物的计算表现优于芳香族化合物，这表明芳香性仍是此类简易力场中难以精准表征的性质。