Continuum Electrostatics: Methods and Applications to Ligand Design and Molecular Recognition

Comment on the Validation of Continuum Electrostatics Models MARCO SCARSI, AMEDEO CAFLISCH Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland Received 4 January 1999; accepted 1 June 1999 ABSTRACT: A validation based on solvation energies (vacuum to water transfer) is not sufficient to justify the use of approximated models of electrostatics to rank ligand/protein complexes. A full validation should be based on energies in solution, i.e., solvation plus vacuum Coulomb energies, because of the anticorrelation between solvation and vacuum energies. The energy in solution is the relevant quantity in simulations of biological macromolecules and complexes. c© 1999 John Wiley & Sons, Inc. J Comput Chem 20: 1533–1536, 1999 Keywords: continuum electrostatics; solvation energy; Poisson equation; thrombin; docking F ast methodologies are needed to estimate sol- vation effects for docking flexible ligands in re- ceptor binding sites. Approximated continuum elec- trostatic approaches are often used, but sometimes a good agreement with the exact solution of the Pois- son equation (finite-difference method 1 ) can origi- nate uniquely from an inappropriate validation. A comprehensive continuum treatment of the electrostatic effects of a high-dielectric solvent in the calculation of ligand-receptor binding energies should include the evaluation of the screened inter- molecular interaction, as well as the receptor and ligand desolvations. The former is the intermolec- ular energy of the complex in solution, whereas the desolvation of a solute molecule is defined as the Correspondence to: A. Caflisch; e-mail: [email protected] Contract/grant sponsor: Swiss National Science Foundation; contract/grant number: 31-53604.98 solute–solvent energy that is lost when part of the surrounding solvent is replaced by molecules with lower polarizability. Desolvation is the only energy term that disfavors the association between two op- posite charges in solution. In this comment, we focus on the screened inter- action between two molecules (e.g., a receptor and a ligand) in a solvent. It can be calculated from the potential solution of the Poisson equation, assuming that one of the two molecules (in the present case the ligand) is an uncharged low dielectric cavity: E int solution = N ∑ i= 1 q i φ ( Er i ) (1) where N is the number of ligand atoms, q i is the partial charge of the ligand atom i,andφ(Er i )is the electrostatic potential generated by the charges of the receptor at the position of atom i.Thisap- proach requires the solution of the Poisson equation Journal of Computational Chemistry, Vol. 20, No. 14, 1533–1536 (1999) c© 1999 John Wiley & Sons, Inc. CCC 0192-8651 / 99 / 141533-04