Improved Accuracy for Constant pH-REMD Simulations through Modification of Carboxylate Effective Radii.

The accuracy of computational models for simulating biomolecules under specific solution pH conditions is critical for properly representing the effect of pH in biological processes. Constant pH (CpH) simulations involving implicit solvent using the AMBER software often incorrectly estimate pKa values of aspartate and glutamate residues due to large effective radii stemming from the presence of dummy protons. These inaccuracies stem from problems in the sampled ensembles of titratable residues that can influence other observable pH-dependent behavior, such as conformational change. We investigate new radii assignments for atoms in titratable residues with carboxylate groups to mitigate the systematic overestimation in the current method. We find that decreased carboxylate radii correspond with increased agreement with experimentally derived pKa values for residues in hen egg-white lysozyme and Δ+PHS variants of staphylococcal nuclease (SNase) and improved conformation state sampling compared to experimentally described expectations of native-like structure. Our CpH simulations suggest that decreasing the effective radii of these carboxylate groups is essential for eliminating a significant source of systematic error that hurts the accuracy of both conformational and protonation state sampling with implicit solvent.