Prediction of pKa shifts in proteins using a combination of molecular mechanical and continuum solvent calculations

✍ Scribed by Bernd Kuhn; Peter A. Kollman; Martin Stahl

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 107 KB
• Volume: 25
• Category: Article
• ISSN: 0192-8651
• DOI: 10.1002/jcc.20111

✦ Synopsis

Abstract

The prediction of pK~a~ shifts of ionizable groups in proteins is of great relevance for a number of important biological phenomena. We present an implementation of the MM‐GBSA approach, which combines molecular mechanical (MM) and generalized Born (GB) continuum solvent energy terms, to the calculation of pK~a~ values of a panel of nine proteins, including 69 individual comparisons with experiment. While applied so far mainly to the calculation of biomolecular binding free energies, we show that this method can also be used for the estimation of protein pK~a~ shifts, with an accuracy around 1 pK~a~ unit, even for strongly shifted residues. Our analysis reveals that the nonelectrostatic terms that are part of the MM‐GBSA free energy expression are important contributors to improved prediction accuracy. This suggests that most of the previous approaches that focus only on electrostatic interactions could be improved by adding other nonpolar energy terms to their free energy expression. Interestingly, our method yields best accuracy at protein dielectric constants of ε~int~ = 2–4, which is in contrast to previous approaches that peak at higher ε~int~ ≥ 8. An important component of our procedure is an intermediate minimization step of each protonation state involving different rotamers and tautomers as a way to explicitly model protein relaxation upon (de)protonation. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1865–1872, 2004