Accuracy of Alternate Nonpolarizable Force Fields for the Determination of Protein-Ligand Binding Affinities Dominated by Cation-π Interactions

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-pi 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-pi 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-pi interactions, most notably with CHARMM36m-NBF.

Automated summary

Modifying Lennard-Jones parameters and utilizing NBFIX corrections in the CHARMM36 force field significantly improves the description of protein-ligand complexes, especially those involving cation-pi interactions. Results show that the optimized CHARMM36m-NBF and CHARMM36-WYF parameters provide more accurate binding free energy calculations compared to the original force fields.