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−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.