Evaluating Force Field Performance in Thermodynamic Calculations of Cyclodextrin Host–Guest Binding: Water Models, Partial Charges, and Host Force Field Parameters

Computational
prediction of noncovalent binding free energies with
methods based on molecular mechanical force fields has become increasingly
routine in drug discovery projects, where they promise to speed the
discovery of small molecule ligands to bind targeted proteins with
high affinity. Because the reliability of free energy methods still
has significant room for improvement, new force fields, or modifications
of existing ones, are regularly introduced with the aim of improving
the accuracy of molecular simulations. However, comparatively little
work has been done to systematically assess how well force fields
perform, particularly in relation to the calculation of binding affinities.
Hardware advances have made these calculations feasible, but comprehensive
force field assessments for protein–ligand sized systems still
remain costly. Here, we turn to cyclodextrin host–guest systems,
which feature many hallmarks of protein–ligand binding interactions
but are generally much more tractable due to their small size. We
present absolute binding free energy and enthalpy calculations, using
the attach-pull-release (APR) approach, on a set of 43 cyclodextrin-guest
pairs for which experimental ITC data are available. The test set
comprises both α- and β-cyclodextrin hosts binding a series
of small organic guests, each with one of three functional groups:
ammonium, alcohol, or carboxylate. Four water models are considered
(TIP3P, TIP4Pew, SPC/E, and OPC), along with two partial charge assignment
procedures (RESP and AM1-BCC) and two cyclodextrin host force fields.
The results suggest a complex set of considerations when choosing
a force field for biomolecular simulations. For example, some force
field combinations clearly outperform others at the binding enthalpy
calculations but not for the binding free energy. Additionally, a
force field combination which we expected to be the worst performer
gave the most accurate binding free energies – but the least
accurate binding enthalpies. The results have implications for the
development of improved force fields, and we propose this test set,
and potential future elaborations of it, as a powerful validation
suite to evaluate new force fields and help guide future force field
development.

基于分子机械力场方法对非共价键结合自由能的计算预测，在药物发现项目中已成为一项日益常规化的技术，它承诺能够加速针对具有高亲和力的靶标蛋白的小分子配体的发现。然而，由于自由能方法在可靠性上仍有显著的提升空间，因此，新的力场或对现有力场的改进，定期被引入以提升分子模拟的准确性。尽管硬件的进步使得这些计算成为可能，但对于蛋白质-配体规模系统的全面力场评估仍成本高昂。在本研究中，我们转向环糊精主-客体系统，这种系统具有许多蛋白质-配体相互作用的特点，但由于其尺寸较小，通常更为易于处理。我们采用附加-拉动-释放（APR）方法，对43个环糊精-客体对进行了绝对结合自由能和焓的计算，这些客体对均对应于有可用实验ITC数据的实验。测试集包括α-和β-环糊精宿主结合一系列具有三种官能团（铵、醇或羧酸盐）的小有机客体。考虑了四种水模型（TIP3P、TIP4Pew、SPC/E和OPC），以及两种部分电荷分配程序（RESP和AM1-BCC）和两种环糊精宿主力场。结果表明，在选择生物分子模拟中的力场时需考虑一系列复杂的因素。例如，某些力场组合在结合焓的计算中明显优于其他力场组合，但在结合自由能的计算中则不然。此外，我们预期表现最差的力场组合给出了最准确的结合自由能——但结合焓的准确性最低。这些结果对改进力场的发展具有重要意义，我们提议此测试集，及其潜在的将来扩展，作为一个强大的验证工具，以评估新的力场，并指导未来的力场发展。