Evaluating Force Field Performance in ThermodynamicCalculations of Cyclodextrin Host–Guest Binding: Water ModelsPartial Charges and Host Force Field Parameters

摘要

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, usingthe attach-pull-release (APR) approach, on a set of 43 cyclodextrin-guestpairs for which experimental ITC data are available. The test setcomprises both α- and β-cyclodextrin hosts binding a seriesof 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 assignmentprocedures (RESP and AM1-BCC) and two cyclodextrin host force fields.The results suggest a complex set of considerations when choosinga force field for biomolecular simulations. For example, some forcefield combinations clearly outperform others at the binding enthalpycalculations but not for the binding free energy. Additionally, aforce field combination which we expected to be the worst performergave the most accurate binding free energies – but the leastaccurate binding enthalpies. The results have implications for thedevelopment of improved force fields, and we propose this test set,and potential future elaborations of it, as a powerful validationsuite to evaluate new force fields and help guide future force fielddevelopment.