Constant pH molecular dynamics in generalized Born implicit solvent

TLDR

The authors propose a constant‑pH molecular dynamics method that uses generalized Born electrostatics to model protonation states. The method employs Monte‑Carlo sampling of protonation states based on GB‑derived energies, applying this framework to four hen‑egg‑white lysozyme crystal structures. Simulations yield pK_a predictions with a 0.82 RMS error, are independent of the starting crystal structure, and reveal a strong correlation between protein conformation and protonation state, underscoring the need to sample protonation states during dynamics. © 2004 Wiley Periodicals, Inc., J Comput Chem 25:2038–2048, 2004.

Abstract

Abstract A new method is proposed for constant pH molecular dynamics (MD), employing generalized Born (GB) electrostatics. Protonation states are modeled with different charge sets, and titrating residues sample a Boltzmann distribution of protonation states as the simulation progresses, using Monte Carlo sampling based on GB‐derived energies. The method is applied to four different crystal structures of hen egg‐white lysozyme (HEWL). pK a predictions derived from the simulations have root‐mean‐square (RMS) error of 0.82 relative to experimental values. Similarity of results between the four crystal structures shows the method to be independent of starting crystal structure; this is in contrast to most electrostatics‐only models. A strong correlation between conformation and protonation state is noted and quantitatively analyzed, emphasizing the importance of sampling protonation states in conjunction with dynamics. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 2038–2048, 2004