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Biophys. J. BioFAST: First Published April 8, 2005. doi:10.1529/biophysj.104.055996
© 2005 by the Biophysical Society.

A more recent version of this article appeared on June 1, 2005.
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BIOPHYSICAL THEORY AND MODELING

Proton binding to proteins: a free energy component analysis using a dielectric continuum model

Georgios Archontis 1* and Thomas Simonson 2

1 Department of Physics, University of Cyprus
2 Ecole Polytechnique

* To whom correspondence should be addressed. E-mail: archonti{at}ucy.ac.cy.

Submitted on November 9, 2004
Revised on December 28, 2004
Accepted on 30 March 2005


  Abstract
Proton binding plays a critical role in protein structure and function. We report pKa calculations for three aspartates in two proteins, using a Linear Response approach, as well as a 'standard' Poisson-Boltzmann (PB) approach. Averaging over conformations from the two endpoints of the proton binding reaction, the protein's atomic degrees of freedom are explicitly modelled. 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 pKa shifts from explicit solvent molecular dynamics simulations, and the pKa shifts from experiment. For thioredoxin Asp26, which has a large pKa upshift, we correctly capture the balance between unfavorable carboxylate desolvation and favorable interactions with a nearby lysine; similarly for RNAse A Asp14, which has a large pKa downshift. For the unshifted thioredoxin Asp20, desolvation by the protein cavity is overestimated by 2.9 pKa units; several effects could explain this. 'Standard' PB 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 pKa's of Asp26 and Asp14.

Key Words: continuum electrostatics, free energy calculations, linear response, pKa calculations, proton binding




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Copyright © 2005 by the Biophysical Society.