Implicit Solvents for the Polarizable Atomic Multipole AMOEBA Force Field

Computational
protein design, ab initio protein/RNA folding, and
protein–ligand screening can be too computationally demanding
for explicit treatment of solvent. For these applications, implicit
solvent offers a compelling alternative, which we describe here for
the polarizable atomic multipole AMOEBA force field based on three
treatments of continuum electrostatics: numerical solutions to the
nonlinear and linearized versions of the Poisson–Boltzmann
equation (PBE), the domain-decomposition conductor-like screening
model (ddCOSMO) approximation to the PBE, and the analytic generalized
Kirkwood (GK) approximation. The continuum electrostatics models are
combined with a nonpolar estimator based on novel cavitation and dispersion
terms. Electrostatic model parameters are numerically optimized using
a least-squares style target function based on a library of 103 small-molecule
solvation free energy differences. Mean signed errors for the adaptive
Poisson–Boltzmann solver (APBS), ddCOSMO, and GK models are
0.05, 0.00, and 0.00 kcal/mol, respectively, while the mean unsigned
errors are 0.70, 0.63, and 0.58 kcal/mol, respectively. Validation
of the electrostatic response of the resulting implicit solvents,
which are available in the Tinker (or Tinker-HP), OpenMM, and Force
Field X software packages, is based on comparisons to explicit solvent
simulations for a series of proteins and nucleic acids. Overall, the
emergence of performative implicit solvent models for polarizable
force fields opens the door to their use for folding and design applications.