Accuracy of Alternate Nonpolarizable Force Fields for the Determination of Protein-Ligand Binding Affinities
Han Liu1, Haohao Fu1, Christophe Chipot2,3
1Research Center for Analytical Sciences, College of Chemistry, and Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China.
Abstract:
Modifying pair-specific Lennard-Jones parameters through the nonbonded FIX (NBFIX) feature of the CHARMM36 force field has proven cost-effective for improving the description of cation-π interactions in biological objects by means of pairwise additive potential energy functions. Here, two sets of newly optimized CHARMM36 force-field parameters including NBFIX corrections, coined CHARMM36m-NBF and CHARMM36-WYF, and the original force fields, namely CHARMM36m and Amber ff14SB, are used to determine the standard binding free energies of seven protein-ligand complexes containing cation-π interactions. Compared with precise experimental measurements, our results indicate that the uncorrected, original force fields significantly underestimate the binding free energies, with a mean error of 5.3 kcal/mol, while the mean errors of CHARMM36m-NBF and CHARMM36-WYF amount to 0.8 and 2.1 kcal/mol, respectively. The present study cogently demonstrates that the use of modified parameters jointly with NBFIX corrections dramatically increases the accuracy of the standard binding free energy of protein-ligand complexes dominated by cation-π interactions, most notably with CHARMM36m-NBF.
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