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 molecularmechanicsPoisson-Boltzmann surface area (MMPBSA) calculations by adoptionof ANI-ML potentials in replacement of MM terms, the use of solvent-accessiblesurface area (SASA) and volume (SAV) values from the Monte Carlo samplingof the probe, and introducing two different interior dielectric constantsfor electrostatic interactions of protein-ligand (P-L)and polar solvation term in the MMPBSA calculations. Our results showthat the Pearson correlation coefficients of MMPBSA-calculated valueswith respect to experimental binding free energies can be drasticallyimproved from 0.48 to 0.90 by adoption of ANI-ML potentials in replacementof MM energy terms in the equation, referred to as ANI-PBSA. Moreover,we show that the SASA/SAV-combined equation in the scaled particletheory (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 variableconstant definitions.