Using DelPhi to Compute Electrostatic Potentials and Assess Their Contribution to Interactions

Assaf Oron1, Haim Wolfson1, Kannan Gunasekaran2, Ruth Nussinov3

1 Tel Aviv University, Tel Aviv, Israel, 2 Laboratory of Experimental and Computational Biology, National Cancer Institute, Frederick, Maryland, 3 Laboratory of Experimental and Computational Biology, SAIC‐Frederick, Frederick, Maryland
Publication Name:  Current Protocols in Bioinformatics
Unit Number:  Unit 8.4
DOI:  10.1002/0471250953.bi0804s02
Online Posting Date:  August, 2003
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library


There is a general agreement that electrostatic interactions play a significant role in the structure and function of biological molecules. However, obtaining quantitative estimation of the electrostatic energy requires computational models that capture the microscopic nature of the heterogeneous environment of macromolecules. This protocol offers elaboration on one of the common methods to calculate the electrostatic energetic contributions using continuum electrostatics. The method involves solving the Poisson‚ÄźBoltzmann (PB) equation numerically and regarding the solute as having a homogenous dielectric constant. In order to apply this method, a three dimensional structure of the molecule derived from experimental data (crystallography, NMR) or modeling techniques is required. The protocol will focus on the DelPhi program (Accelrys Inc. San Diego), which is one of the most common programs used for the estimation of electrostatic free energy contribution. A simple procedure of assigning criteria and parameters (charge distribution, solvent and solute dielectric constants, iterations, grid resolution, etc) enables one to illustrate an electrostatic potential map and estimate the electrostatic free energy, although with limited accuracy.

PDF or HTML at Wiley Online Library

Table of Contents

  • Guidelines for Understanding Results
  • Commentary
  • Literature Cited
  • Figures
PDF or HTML at Wiley Online Library


Basic Protocol 1:

  Necessary Resources
  • Silicon Graphics IRIS workstations
  • Insight II modeling program and DelPhi module (Accelrys; see Internet Resources) or
  • DelPhi stand‐alone program (Columbia University; see Internet Resources)
  • Three‐dimensional structure of the unbound and bound proteins in PDB or other Insight II–readable format
PDF or HTML at Wiley Online Library



Literature Cited

   Ajay, A. and Murcko, M.A. 1995. Computational methods to predict binding free energy in ligand‐receptor complexes. J. Med. Chem. 38:4953‐4967.
   Alexov, E.G. and Gunner, M.R. 1999. Calculated protein and proton motions coupled to electron transfer: Electron transfer from QA to QB in bacterial photosynthetic reaction centers. Biochemistry 38:8253‐8270.
   Andrews, P.R., Craik, D.J., and Martin, J.L. 1984. Functional group contributions to drug‐receptor interactions. J. Med. Chem. 27:1648‐1657.
   Bash, P.A., Singh, U.C., Brown, F.K., Langridge, R., and Kollman, P.A. 1987. Free energy calculations by computer simulation. Science 235:574‐576.
   Beveridge, D.L. and DiCapua, F.M. 1989. Free energy via molecular simulation: Applications to chemical and biomolecular systems. Biophys. Chem. 18:431‐492.
   Brooks, B.R., Bruccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S., and Karplus, M. 1983. CHARMM: A program for macromolecular energy minimization and dynamic calculations. J. Comput. Chem. 4:187‐217.
   Dominy, B. and Brooks, III, C.L. 1999. Development of a generalized Born model parameterization for proteins and nucleic acids. J. Phys. Chem. 103:3765‐3773.
   Froloff, N., Windemuth, A., and Honig, B.H. 1997. On the calculation of binding free energies using continuum methods: Application to MHC class I protein‐peptide interactions. Protein Science 6:1293‐1301.
   Gilson, M.K. and Honig, B.H. 1986. The dielectric constant of a folded protein. Biopolymers 25:2097‐2119.
   Gilson, M.K. and Honig, B.H. 1988. Energetics of charge‐charge interactions in proteins. Proteins 3:32‐52.
   Honig, B.H., Sharp, K., and Yang, A.S. 1993. Macroscopic models of aqueous solution: Biological and chemical applications. J. Phys. Chem. 97:1101‐1109.
   Klapper, I., Hagstrom, R., Fine, R., Sharp, K., and Honig, B.H. 1986. Focusing of electric fields in the active site of Cu‐Zn superoxide dismutase: Effects of ionic strength and amino‐acid modification. Proteins 1:47‐59.
   McCammon, J.A. 1987. Computer‐aided molecular design. Science 238: 486‐491.
   Miyamoto, S. and Kollman, P.A. 1993. Absolute and relative binding free energy calculations of the interaction of biotin and its analogs with streptavidin using molecular dynamics/free energy perturbation approaches. Proteins 16:226‐245.
   Nicholls, A. and Honig, B.H. 1991. A rapid finite difference algorithm, utilizing successive over‐relaxation to solve Poisson‐Boltzmann equations. J. Comput. Chem. 12:435‐445.
   Nielsen, J.E., Andersen, K.V., Honig, B., Hooft, R.W.W., Klebe, G., Vriend, G., and Wade, R.C. 1999. Improving macromolecular electrostatics calculations. Protein Eng. 12:657‐662.
   Pearlman, D.A. and Rao, G.B. 1998. Free energy calculation: Methods and applications. In The Encyclopedia of Computational Chemistry, vol. 2. (Schleyer, P.v.R., Jorgensen, W.L., Schaefer III, H.F., Schreiner, P.R., and Thiel, W., eds.), pp. 1053‐1058. John Wiley & Sons, Chichester, U.K.
   Rocchia, W., Alexov, E., and Honig, B. 2001. Extending the applicability of nonlinear Poisson‐Boltzmann equation: Multiple dielectric constants and multivalent ions. J. Phys. Chem. B. 105:6507‐6514.
   Schutz, C.N. and Warshel, A. 2001. What are the dielectric “constants” of proteins and how to validate electrostatic models? Proteins 44:400‐417.
   Sheinerman, F.B., Norel, R., and Honig, B. 2000. Electrostatic aspects of protein‐protein interactions. Curr. Opin. Struct. Biol. 10:153‐159.
   Straatsma, T.P. and McCammon, J.A. 1991. Theoretical calculations of relative affinities of binding. Method Enzymol. 202:497‐511.
   Williams, D.H., Cox, J.P.L., Doig, A.J., Gardner, M., Gerhard. U., Kaye, P.T., Lal, A.R., Nicholls, I.A., Salter, C.J., and Mitchell, R.C. 1991. Toward the semiquantitative estimation of binding constants. Guides for peptide‐peptide binding in aqueous solution. J. Am. Chem. Soc. 113:7020‐7030.
   Tobias, D.J. 2001. Electrostatic calculations: Recent methodological advances and applications to membranes. Curr. Opin. Struct. Biol. 11:253‐261.
Key Reference
   Honig et al., 1993. See above.
  Covers the fundamental theoretical and practical aspects of DelPhi.
Internet Resources
  Accelrys Web site.
  Web site to obtain the source code of DelPhi program, available at the Department of Biochemistry, Columbia University.
PDF or HTML at Wiley Online Library