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

Abstract

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.

Figure 1

Experimental and calculated binding free energies by MMPBSA using SASA only/SPT regimes for nonpolar contribution where ε_int = 2.1 for electrostatic and polar solvation terms.

Figure 2

Relationship between SASA (or SAV enclosed by SASA) and E_disp (calculated by the integration of SASA). The values are of averages of PL–P–L differences over 100 MD snapshots.

Figure 3

Illustration of pore volume produced by Zeo++ showing (a) covered regions in PCAV and POAV definitions and (b) how we calculated the molecular surface from pore volume.

Figure 4

Comparison of MMPBSA_E and ANI_PBSAe by using SASA only and SPT regimes.

Figure 5

Comparison of the single-valued vs two-valued ε_int for Coulombic (P–L) and polar solvation terms, respectively.