Constant-pH molecular dynamics simulations have, until recently, been mostly regarded as a small niche field dedicated to the study of small to medium sized atomistic systems. This has largely been due to either implementation details (e.g. poor parallelization) or else specialization of the underlying method (e.g. reliance on implicit solvent or approximate electrostatics). In this work we demonstrate how a constant-pH algorithm based on nonequilibrium molecular dynamics/Monte Carlo overcomes these obstacles and achieves both scale and accuracy on petascale computer clusters.<br/>The implementation inherits the scaling behavior of the NAMD software package with standard long-range electrostatics (i.e. particle mesh Ewald) and explicit solvent. The efficiency of the method is further improved by recent proposals regarding the handling of momentum reversals and titration of residues with inherent pKa values that are very different from the pH.<br/>Analyzing the nonequilibrium work can also be used to optimize the switching times between protonation states. Illustrative applications are presented on globular and membrane protein systems composed of &gt;50,000 atoms.

Constant-pH simulations on capability class computers: First applications

253rd National Meeting (2017)

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