title: Coupled molecular dynamics and continuum electrostatic method to compute the ionization pKa's of proteins as a function of pH. Test on a large set of proteins.
abstract: A computational method, to predict the pKa values of the ionizable residues Asp, Glu, His, Tyr, and Lys of proteins, is presented here. Calculation of the electrostatic free-energy of the proteins is based on an efficient version of a continuum dielectric electrostatic model. The conformational flexibility of the protein is taken into account by carrying out molecular dynamics simulations of 10 ns in implicit water. The accuracy of the proposed method of calculation of pKa values is estimated from a test set of experimental pKa data for 297 ionizable residues from 34 proteins. The pKa-prediction test shows that, on average, 57, 86, and 95% of all predictions have an error lower than 0.5, 1.0, and 1.5 pKa units, respectively. This work contributes to our general understanding of the importance of protein flexibility for an accurate computation of pKa, providing critical insight about the significance of the multiple neutral states of acid and histidine residues for pKa-prediction, and may spur significant progress in our effort to develop a fast and accurate electrostatic-based method for pKa-predictions of proteins as a function of pH.
authors.affiliation: a Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Science , Lavrentiev Avenue 8, Novosibirsk 630090 , Russia.|b Novosibirsk State University , Novosibirsk 630090 , Russia.|c Baker Laboratory of Chemistry and Chemical Biology , Cornell University , Ithaca 14853-1301 , NY , USA.
authors.forename: Yury N
authors.initials: YN
authors.lastname: Vorobjev
authors.affiliation: c Baker Laboratory of Chemistry and Chemical Biology , Cornell University , Ithaca 14853-1301 , NY , USA.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Scheraga
authors.affiliation: d IMASL-CONICET, Universidad Nacional de San Luis , Ejército de Los Andes 950, San Luis 5700 , Argentina.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Vila
mesh_terms: D019277:Entropy; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009113:Muramidase / Q000737:chemistry*; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D011506:Proteins; D009113:Muramidase
keywords: continuum dielectric model; molecular dynamics; pKa-predictions; protein ionization