title: Charge-Neutral Constant pH Molecular Dynamics Simulations Using a Parsimonious Proton Buffer.
abstract: In constant pH molecular dynamics simulations, the protonation states of titratable sites can respond to changes of the pH and of their electrostatic environment. Consequently, the number of protons bound to the biomolecule, and therefore the overall charge of the system, fluctuates during the simulation. To avoid artifacts associated with a non-neutral simulation system, we introduce an approach to maintain neutrality of the simulation box in constant pH molecular dynamics simulations, while maintaining an accurate description of all protonation fluctuations. Specifically, we introduce a proton buffer that, like a buffer in experiment, can exchange protons with the biomolecule enabling its charge to fluctuate. To keep the total charge of the system constant, the uptake and release of protons by the buffer are coupled to the titration of the biomolecule with a constraint. We find that, because the fluctuation of the total charge (number of protons) of a typical biomolecule is much smaller than the number of titratable sites of the biomolecule, the number of buffer sites required to maintain overall charge neutrality without compromising the charge fluctuations of the biomolecule, is typically much smaller than the number of titratable sites, implying markedly enhanced simulation and sampling efficiency.
authors.affiliation: Nanoscience Center and Department of Biological and Environmental Sciences, University of Jyväskylä , P. O. Box 35, 40014 Jyväskylä, Finland.
authors.forename: Serena
authors.initials: S
authors.lastname: Donnini
authors.affiliation: Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry , Am Faßberg 11, 37077 Göttingen, Germany.
authors.forename: R Thomas
authors.initials: RT
authors.lastname: Ullmann
authors.affiliation: Nanoscience Center and Department of Chemistry, University of Jyväskylä , P. O. Box 35, 40014 Jyväskylä, Finland.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Groenhof
authors.affiliation: Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry , Am Faßberg 11, 37077 Göttingen, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Grubmüller
mesh_terms: D002021:Buffers; D006863:Hydrogen-Ion Concentration; D056004:Molecular Dynamics Simulation; D011506:Proteins / Q000737:chemistry*; D011522:Protons; D013816:Thermodynamics
chemical_list: D002021:Buffers; D011506:Proteins; D011522:Protons