title: Proton binding to proteins: a free-energy component analysis using a dielectric continuum model.
abstract: Proton binding plays a critical role in protein structure and function. We report pK(a) calculations for three aspartates in two proteins, using a linear response approach, as well as a "standard" Poisson-Boltzmann approach. Averaging over conformations from the two endpoints of the proton-binding reaction, the protein's atomic degrees of freedom are explicitly modeled. Treating macroscopically the protein's electronic polarizability and the solvent, a meaningful model is obtained, without adjustable parameters. It reproduces qualitatively the electrostatic potentials, proton-binding free energies, Marcus reorganization free energies, and pK(a) shifts from explicit solvent molecular dynamics simulations, and the pK(a) shifts from experiment. For thioredoxin Asp-26, which has a large pK(a) upshift, we correctly capture the balance between unfavorable carboxylate desolvation and favorable interactions with a nearby lysine; similarly for RNase A Asp-14, which has a large pK(a) downshift. For the unshifted thioredoxin Asp-20, desolvation by the protein cavity is overestimated by 2.9 pK(a) units; several effects could explain this. "Standard" Poisson-Boltzmann methods sidestep this problem by using a large, ad hoc protein dielectric; but protein charge-charge interactions are then incorrectly downscaled, giving an unbalanced description of the reaction and a large error for the shifted pK(a) values of Asp-26 and Asp-14.
authors.affiliation: Department of Physics, University of Cyprus, Nicosia. archonti@ucy.ac.cy
authors.forename: Georgios
authors.initials: G
authors.lastname: Archontis
authors.forename: Thomas
authors.initials: T
authors.lastname: Simonson
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry; D055592:Biophysical Phenomena; D001703:Biophysics; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D011522:Protons; D012260:Ribonucleases / Q000737:chemistry; D055672:Static Electricity; D013816:Thermodynamics; D013879:Thioredoxins / Q000737:chemistry
chemical_list: D011506:Proteins; D011522:Protons; D001224:Aspartic Acid; D013879:Thioredoxins; D012260:Ribonucleases