title: Origin of pKaShifts of Internal Lysine Residues in SNase Studied Via Equal-Molar VMMS Simulations in Explicit Water.
abstract: Protein internal ionizable groups can exhibit large shifts in pKavalues. Although the environment and interaction changes have been extensively studied both experimentally and computationally, direct calculation of pKavalues of these internal ionizable groups in explicit water is challenging due to energy barriers in solvent interaction and in conformational transition. The virtual mixture of multiple states (VMMS) method is a new approach designed to study chemical state equilibrium. This method constructs a virtual mixture of multiple chemical states in order to sample the conformational space of all states simultaneously and to avoid crossing energy barriers related to state transition. By applying VMMS to 25 variants of staphylococcal nuclease with lysine residues at internal positions, we obtained the pKavalues of these lysine residues and investigated the physics underlining the pKashifts. Our calculation results agree reasonably well with experimental measurements, validating the VMMS method for pKacalculation and providing molecular details of the protonation equilibrium for protein internal ionizable groups. Based on our analyses of protein conformation relaxation, lysine side chain flexibility, water penetration, and the microenvironment, we conclude that the hydrophobicity of the microenvironment around the lysine side chain (which affects water penetration differently for different protonation states) plays an important role in the pKashifts.
authors.affiliation: Laboratory of Computational Biology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH) , Bethesda, Maryland 20892, United States.
authors.forename: Xiongwu
authors.initials: X
authors.lastname: Wu
authors.affiliation: Laboratory of Computational Biology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH) , Bethesda, Maryland 20892, United States.
authors.forename: Juyong
authors.initials: J
authors.lastname: Lee
authors.affiliation: Laboratory of Computational Biology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH) , Bethesda, Maryland 20892, United States.
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Brooks
mesh_terms: D006863:Hydrogen-Ion Concentration; D008239:Lysine / Q000737:chemistry*; D008836:Micrococcal Nuclease / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D014867:Water; D008836:Micrococcal Nuclease; D008239:Lysine