A generalized Kirkwood implicit solvent for the polarizable AMOEBA protein model

Abstract

Computational simulation of biomolecules can provide important insights into protein design, protein-ligand binding interactions, and ab initio biomolecular folding, among other applications. Accurate treatment of the solvent environment is essential in such applications, but the use of explicit solvents can add considerable cost. Implicit treatment of solvent effects using a dielectric continuum model is an attractive alternative to explicit solvation since it is able to describe solvation effects without the inclusion of solvent degrees of freedom. Previously, we described the development and parameterization of implicit solvent models for small molecules. Here, we extend the parameterization of the generalized Kirkwood (GK) implicit solvent model for use with biomolecules described by the AMOEBA force field via the addition of corrections to the calculation of effective radii that account for interstitial spaces that arise within biomolecules. These include element-specific pairwise descreening scale factors, a short-range neck contribution to describe the solvent-excluded space between pairs of nearby atoms, and finally tanh-based rescaling of the overall descreening integral. We then apply the AMOEBA/GK implicit solvent to a set of ten proteins and achieve an average coordinate root mean square deviation for the experimental structures of 2.0 Å across 500 ns simulations. Overall, the continued development of implicit solvent models will help facilitate the simulation of biomolecules on mechanistically relevant timescales.

Constant-pH Simulations with the Polarizable Atomic Multipole AMOEBA Force Field

“…The success of this algorithm in predicting titration states of peptides in a crystalline environment using the traditional parametrization of a peptide in water suggests that this model will be suitable for p K a prediction in proteins under PME. Future work will incorporate CpHMD into AMOEBA protein simulations based on the generalized Kirkwood implicit solvent. , …”

“…Future work will incorporate CpHMD into AMOEBA protein simulations based on the generalized Kirkwood implicit solvent. 63 , 64 …”

Force Field X: A computational microscope to study genetic variation and organic crystals using theory and experiment

“…The Potential package supports calculation of long-range electrostatics using particle-mesh Ewald 35–37 (PME) summation with novel support for space group symmetry 1 and offers continuum treatment of solvent via our GK model. 3,33–35 The FFX commands defined within the Potential package are listed in Fig. 1 .…”

“…Currently, the FFX implementation of GK implicit solvent has been validated for protein simulations with work ongoing to support nucleic acids. 3 …”

“…For example, FFX debuted the first implementation of x-ray crystallography refinement using the polarizable atomic multipole AMOEBA force field, the first constant-pH molecular dynamics (MD) support for a polarizable force field, 32 and the generalized Kirkwood (GK) implicit solvent models. 3,33–35 FFX also implements efficient inclusion of space group symmetry into long-range electrostatics via particle-mesh Ewald (PME) summation 1,35–37 and orthogonal space tempering (OST) for the calculation of free energy differences. 6,8,38,39 It can also perform global optimization using dead-end 40 (and Goldstein 41 ) elimination for target functions that include higher-order many-body terms 11,43 and dual topology methods to compute free energy differences between potential energy models.…”