Evaluation of Electrostatic Interactions

David F. Green1, Bruce Tidor1

1 Massachusetts Institute of Technology, Cambridge, Massachusetts
Publication Name:  Current Protocols in Bioinformatics
Unit Number:  Unit 8.3
DOI:  10.1002/0471250953.bi0803s02
Online Posting Date:  August, 2003
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Described here are several computational procedures for the analysis of electrostatic interactions in molecular complexes, all based on a continuum model of solvation. The first section describes how to compute the residual potential, a measure of how electrostatically complementary a ligand is for its receptor. The second procedure describes electrostatic component analysis, a method by which the electrostatic contribution to the binding free energy can be broken up into terms directly attributable to individual chemical groups. Finally, electrostatic affinity optimization is described. This procedure is particularly useful in determining what portions of a ligand are the most suboptimal, and thus provide the greatest opportunity for the design of improvements.

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Table of Contents

  • Basic Protocol 1: Analysis of Electrostatic Complementarity
  • Basic Protocol 2: Electrostatic Component Analysis
  • Basic Protocol 3: Electrostatic Affinity Optimization
  • Guidelines for Understanding Results
  • Commentary
  • Literature Cited
  • Figures
  • Tables
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Basic Protocol 1: Analysis of Electrostatic Complementarity

  Necessary Resources
  • Silicon Graphics (SGI) computer running the IRIX operating system.
  • Scripts and GRASP macros for computing and processing electrostatic potentials (http://web.mit.edu/tidor/www/residual)
  • GRASP (Nicholls et al., ; http://trantor.bioc.columbia.edu/grasp) or equivalent software capable of displaying electrostatic potentials on a molecular surface
  • PDB‐format coordinate file with all chains of the ligand labeled A and all chains of the receptor labeled B
  • DelPhi‐format charge and atomic radius files (Fig. A and B) for the complex of interest
  • Several such files are included with GRASP.
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Literature Cited

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   Bashford, D. and Karplus, M. 1990. pKa's of ionizable groups in proteins: Atomic detail from a continuum electrostatic model. Biochemistry 29:10219‐10225.
   Chong, L.T., Dempster, S.E., Hendsch, Z.S., Lee, L.‐P., and Tidor, B. 1998. Computation of electrostatic complements to proteins: A case of charge stabilized binding. Protein Sci. 7:206‐210.
   Chothia, C. 1974. Hydrophobic bonding and accessible surface area in proteins. Nature (London) 248:338‐339.
   Chothia, C. and Janin, J. 1975. Principles of protein–protein recognition. Nature (London) 256:705‐708.
   Davis, M.E. and McCammon, J.A. 1990. Electrostatics in biomolecular structure and dynamics. Chem. Rev. 90:509‐521.
   Froloff, N., Windemuth, A., and Honig, B. 1997. On the calculation of binding free energies using continuum methods: Application to MHC class I protein–peptide interactions. Protein Sci. 6:1293‐1301.
   Gilson, M.K. and Honig, B.H. 1987. Calculation of electrostatic potentials in an enzyme active site. Nature (London) 330: 84‐86.
   Gilson, M.K. and Honig, B. 1989. Destabilization of an alpha‐helix‐bundle protein by helix dipoles. Proc. Natl. Acad. Sci. U.S.A. 86:1524‐1528.
   Gilson, M.K., Sharp, K.A., and Honig, B.H. 1988. Calculating the electrostatic potential of molecules in solution: Method and error assessment. J. Comput. Chem. 9:327‐335.
   Gilson, M.A., Given, J.A., Bush, B.L., and McCammon, J.A. 1997. The statistical‐thermodynamic basis for computation of binding affinities: A critical review. Biophys. J. 72:1047‐1069.
   Hendsch, Z.S. and Tidor, B. 1994. Do salt bridges stabilize proteins? A continuum electrostatics analysis. Protein Sci. 3:211‐226.
   Hendsch, Z.S. and Tidor, B. 1999. Electrostatic interactions in the GCN4 leucine zipper: Substantial contributions arise from intramolecular interactions enhanced on binding. Protein Sci. 8:1381‐1392.
   Hendsch, Z.S., Jonsson, T., Sauer, R.T., and Tidor, B. 1996. Protein stabilization by removal of unsatisfied polar groups: Computational approaches and experimental tests. Biochemistry 35:7621‐7625.
   Kangas, E. and Tidor, B. 1998. Optimizing electrostatic affinity in ligand–receptor binding: Theory, computation, and ligand properties. J. Chem. Phys. 109:7522‐7545.
   Kangas, E. and Tidor, B. 1999. Charge optimization leads to favorable electrostatic binding free energy. Phys. Rev. E 59:5958‐5961.
   Kangas, E. and Tidor, B. 2000. Electrostatic specificity in molecular ligand design. J. Chem. Phys. 112:9120‐9131.
   Kangas, E. and Tidor, B. 2001. Electrostatic complementarity at ligand binding sites: Application to chorismate mutase. J. Phys. Chem. B. 105:880‐888.
   Lee, L.‐P. and Tidor, B. 1997. Optimization of electrostatic binding free energy. J. Chem. Phys. 106:8681‐8690.
   Lee, L.‐P. and Tidor, B. 2001a. Barstar is electrostatically optimized for tight binding to barnase. Nat. Struct. Biol. 8:73‐76.
   Lee, L.‐P. and Tidor, B. 2001b. Optimization of binding electrostatics: Charge complementarity in the barnase‐barstar protein complex. Protein Sci. 10:362‐377.
   Misra, V.K., Sharp, K.A., Friedman, R.A., and Honig, B. 1994. Salt effects on ligand–DNA binding: Minor groove binding antibiotics. J. Mol. Biol. 238:245‐263.
   Misra, V.K., Hecht, J.L., Yang, A.‐S., and Honig, B. 1998. Electrostatic contributions to the binding free energy of the λ cI repressor to DNA. Biophys. J. 75:2262‐2273.
   Mohan, V., Davis, M.E., McCammon, J.A., and Pettitt, B.M. 1992. Continuum model calculations of solvation free energies: Accurate evaluation of electrostatic contributions. J. Phys. Chem. 96:6428‐6431.
   Nicholls, A., Sharp, K.A., and Honig, B. 1991. Protein folding and association: Insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins: Struct. Funct. Genet. 11:281‐296.
   Nohaile, M.J., Hendsch, Z.S., Tidor, B., and Sauer, R.T. 2001. Altering dimerization specificity by changes in surface electrostatics. Proc. Natl. Acad. Sci. U.S.A. 98:3109‐3114.
   Potter, M.J., Gilson, M.K., and McCammon, J.A. 1994. Molecule pK(a) prediction with continuum electrostatics. J. Am. Chem. Soc. 116:10298‐10299.
   Sarkar, C.A., Lowenhaupt, K., Horan, T., Boone, T.C., Tidor, B., and Lauffenbuger, D.A. 2002. Rational cytokine design for increased lifetime and enhanced potency using pH‐activated “histidine switching.” Nat. Biotech. 20:908‐913.
   Sharp, K.A. and Honig, B. 1990. Electrostatic interactions in macromolecules: Theory and applications. Annu. Rev. Biophys. Biophys. Chem. 19: 301‐332.
   Sharp, K.A., Nicholls, A., Fine, R.F., and Honig, B. 1991. Reconciling the magnitude of the microscopic and macroscopic hydrophobic effects. Science 252:106‐109.
   Spector, S., Wang, M.H., Carp, S.A., Robblee, J., Hendsch, Z.S., Fairman, R., Tidor, B., and Raleigh, D.P. 2000. Rational modification of protein stability by the mutation of charged surface residues. Biochemistry 39:872‐879.
   Sulea, T. and Purisima, E.O. 2001. Optimizing ligand charges for maximum binding affinity. A solvated interaction energy approach. J. Phys. Chem. B 105:889‐899.
   van Vlijmen, H.W.T., Schaefer, M., and Karplus, M. 1998. Improving the accuracy of protein pK(a) calculations: Conformational averaging versus the average structure. Proteins 33:145‐158.
   Vanderbei, R.J. 1999. LOQO: An interior‐point code for quadratic programing. Optimization Methods and Software 12:451‐454.
   Warwicker, J. and Watson, H.C. 1982. Calculation of the electric potential in the active site cleft due to α‐helix dipoles. J. Mol. Biol. 157:671‐679.
   Xiao, L. and Honig, B. 1999. Electrostatic contributions to the stability of hyperthermophilic proteins. J. Mol. Biol. 289:1435‐1444.
   Yang, A.S., Gunner, M.R., Sampogna, R., Sharp, K., and Honig, B. 1993. On the calculation of pK(a)s in proteins. Proteins 15:252‐265.
   Zacharias, M., Luty, B.A., Davis, M.E., and McCammon, J.A. 1992. Poisson–Boltzmann analysis of the lambda‐repressor‐operator interaction. Biophys. J. 63:1280‐1285.
Key References
   Hendsch and Tidor, 1999. See above.
  Contains a detailed description of the implementation of component analysis and its application to the GCN4 leucine zipper.
   Lee and Tidor, 1997. See above.
  Outlines the theory behind the optimization of electrostatic binding free energy.
   Kangas and Tidor, 1998. See above.
  A detailed description of the electrostatic optimization procedure, including a definition of electrostatic complementarity.
Internet Resources
  Obtaining the Residual Potential Web site.
  The Grasp Web site.
  The DelPhi Web site.
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