Revisiting MMPBSA by Adoption of MC-Based Surface Area/Volume, ANI-ML Potentials, and Two-Valued Interior Dielectric Constant

Here, we report the accuracy improvements of molecular
mechanics
Poisson–Boltzmann surface area (MMPBSA) calculations by adoption
of ANI-ML potentials in replacement of MM terms, the use of solvent-accessible
surface area (SASA) and volume (SAV) values from the Monte Carlo sampling
of the probe, and introducing two different interior dielectric constants
for electrostatic interactions of protein–ligand (P–L)
and polar solvation term in the MMPBSA calculations. Our results show
that the Pearson correlation coefficients of MMPBSA-calculated values
with respect to experimental binding free energies can be drastically
improved from 0.48 to 0.90 by adoption of ANI-ML potentials in replacement
of MM energy terms in the equation, referred to as ANI-PBSA. Moreover,
we show that the SASA/SAV-combined equation in the scaled particle
theory (SPT) can be a better choice to model nonpolar solvation term,
reaching nearly the same accuracy by ANI-PBSA calculations. Finally,
we introduce two different values of interior dielectric constants,
which could be an alternative strategy between the single and variable
constant definitions.