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Proton Binding to Proteins: A Free-Energy Component Analysis Using a Dielectric Continuum Model

Georgios Archontis ^* and Thomas Simonson 

^* Department of Physics, University of Cyprus, PO20537, CY1678, Nicosia, Cyprus; and Laboratoire de Biochimie (UMR7654 du CNRS), Department of Biology, Ecole Polytechnique, 91128 Palaiseau, France

Correspondence: Address reprint requests to Georgios Archontis, E-mail: archonti{at}ucy.ac.cy; or Thomas Simonson, E-mail: thomas.simonson{at}polytechnique.fr.

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.

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