A generalized Kirkwood implicit solvent for the polarizable AMOEBA protein model.

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.

AudioGene: refining the natural history of KCNQ4, GSDME, WFS1, and COCH-associated hearing loss.

Autosomal dominant non-syndromic hearing loss (ADNSHL) displays gene-specific progression of hearing loss, which is amenable to sequential audioprofiling. We sought to refine the natural history of ADNSHL by examining audiometric data in 5-year increments. 2175 audiograms were included from four genetic causes of ADNSHL-KCNQ4 (DFNA2), GSDME (DFNA5), WFS1 (DFNA6/14/38), and COCH (DFNA9). Annual threshold deterioration (ATD) was calculated for each gene: for the speech-frequency pure tone average, the ATD, respectively, was 0.72 dB/year, 0.94 dB/year, 0.53 dB/year, and 1.41 dB/year, with the largest drops occurring from ages 45-50 (0.89 dB/year; KCNQ4), 5-10 (1.42 dB/year; GSDME), 40-45 (0.83 dB/year; WFS1), and 50-55 (2.09 dB/year; COCH). 5-year interval analysis of audiograms reveals the gene specific natural history of KCNQ4, GSDME, WFS1 and COCH-related progressive hearing loss. Identifying ages at which hearing loss is most rapid informs clinical care and patient expectations. Natural history data are also essential to define outcomes of clinical trials that test novel therapies designed to correct or ameliorate these genetic forms of hearing loss.

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.