Structure‐Based pKa Calculations Using Continuum Electrostatics Methods

Carolyn A. Fitch1, Bertrand García‐Moreno E.1

1 Johns Hopkins University, Baltimore, Maryland
Publication Name:  Current Protocols in Bioinformatics
Unit Number:  Unit 8.11
DOI:  10.1002/0471250953.bi0811s16
Online Posting Date:  January, 2007
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Electrostatic free energy is useful for correlating structure with function in proteins in which ionizable groups play essential functional roles. To this end, the pKa values of ionizable groups must be known and their molecular determinants must be understood. Structure‐based calculations of electrostatic energies and pKa values are necessary for this purpose. This unit describes protocols for pKa calculations with continuum electrostatics methods based on the numerical solution of the linearized Poisson‐Boltzmann equation by the method of finite differences. Critical discussion of key parameters, approximations, and shortcomings of these methods is included. Two protocols are described for calculations with methods modified empirically to maximize agreement between measured and calculated pKa values. Applied judiciously, these methods can contribute useful and novel insight into properties of surface ionizable groups in proteins.

Keywords: pKa calculations; continuum electrostatics; finite difference; Poisson‐Boltzmann; UBHD

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Table of Contents

  • Basic Protocol 1: Calculating pKa Values Using the FDPB Method and the Single‐Site Charge Model (FDPB/SS)
  • Alternate Protocol 1: Calculating pKa Values Using the FDPB Method and the Full Charge Model (FDPB/F)
  • Guidelines for Understanding Results
  • Commentary
  • Literature Cited
  • Figures
  • Tables
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Key References
   Davis et al., 1991. See above.
  The above references contain a description of methodology for FDPB calculations with UHBD.
   Madura et al., 1995. See above.
  The above references contain reviews of PB and FDPB methods.
   Antosiewicz et al., 1996a. See above.
  The above references contain in depth discussions of problems of protein reorganization.
   Simonson, 2003. See above.
   Ullman and Knapp, 1999. See above.
   Garcia‐Moreno and Fitch, 2004. See above.
   Archontis and Simonson, 2005. See above.
   Sham et al., 1997. See above.
   Simonson et al., 1999. See above.
   Schutz and Warshel, 2001. See above.
   Simonson et al., 2004. See above.
Internet Resources
   See Table .
  Prof. Jens Nielsen's website discusses many aspects of pKa calculations. Tools are available at this website for calculations and analysis of H+ titration curves.
  Explanation of MCCE method
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