The stochastic titration method for performing constant-pH molecular dynamics (MD) simulations results from combining two usually independent methods: (1) molecular mechanics/dynamics (MM/MD) to sample the conformational equilibrium of a solute molecule with fixed protonation; (2) Poisson-Boltzmann/Monte Carlo (PB/MC) to sample the protonation equilibrium of that solute with fixed conformation. Here we discuss two limitations inherited from the underlying MM/MD and PB/MC methods that may be hindering the progression of constant-pH MD toward an unprecedented level of accuracy. The first discussed limitation is the ill-defined nature of model compounds in PB calculations, both in terms of molecular definition and pKa value; a solution is proposed that improves theoretical consistency and pKa predictions. The second limitation is the eventual distortion that MM force fields may impart into the structure in addition to the intended reorganization to (de)protonation events; the results indicate accumulation of small distortions with detrimental effects on pKa prediction.

Inherited problems of the stochastic titration method for constant-pH molecular dynamics

244th National Meeting (2012)

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