title: Constant pH Molecular Dynamics in Explicit Solvent with Enveloping Distribution Sampling and Hamiltonian Exchange.
abstract: We present a new computational approach for constant pH simulations in explicit solvent based on the combination of the enveloping distribution sampling (EDS) and Hamiltonian replica exchange (HREX) methods. Unlike constant pH methods based on variable and continuous charge models, our method is based on discrete protonation states. EDS generates a hybrid Hamiltonian of different protonation states. A smoothness parametersis used to control the heights of energy barriers of the hybrid-state energy landscape. A smallsvalue facilitates state transitions by lowering energy barriers. Replica exchange between EDS potentials with differentsvalues allows us to readily obtain a thermodynamically accurate ensemble of multiple protonation states with frequent state transitions. The analysis is performed with an ensemble obtained from an EDS Hamiltonian without smoothing,s= ∞, which strictly follows the minimum energy surface of the end states. The accuracy and efficiency of this method is tested on aspartic acid, lysine, and glutamic acid, which have two protonation states, a histidine with three states, a four-residue peptide with four states, and snake cardiotoxin with eight states. The pKavalues estimated with the EDS-HREX method agree well with the experimental pKavalues. The mean absolute errors of small benchmark systems range from 0.03 to 0.17 pKaunits, and those of three titratable groups of snake cardiotoxin range from 0.2 to 1.6 pKaunits. This study demonstrates that EDS-HREX is a potent theoretical framework, which gives the correct description of multiple protonation states and good calculated pKavalues.
authors: Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Juyong
authors: J
authors: Lee
authors: Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Benjamin T
authors: BT
authors: Miller
authors: Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland 20892, United States ; Department of Biophysics, Johns Hopkins University , Baltimore, Maryland, United States.
authors: Ana
authors: A
authors: Damjanović
authors: Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Bernard R
authors: BR
authors: Brooks