Electrostatic complementarity between proteins and ligands. 3. Structural basis

Abstract

Electrostatic potential complementarity between ligands and their receptor sites is evaluated by the superposition of the electrostatic potential, generated by the receptor, onto the ligand potential over the ligand van der Waals surface. We would like to examine which structural factors generate this pattern of superposition. Example studies suggest that in many ligand-protein pairs, there exist principal formal charges on each molecule, largely responsible for the electrostatic potential complementarity observed. Electrostatic potential complementarity depends on the relative disposition of these principal charges and the ligand van der Waals surface. Simple mathematical models were constructed to predict the complementarity solely from structural considerations. The essential conditions for electrostatic potential complementarity were elucidated. These can be used in ligand design strategies to obtain an electrostatically optimal ligand.

Electrostatic complementarity between proteins and ligands. 1. Charge disposition, dielectric and interface effects

“…Nakamura and co-workers [2,38] were the first to attempt quantification. Nevertheless, their method suffers from one drawback.…”

“…The second paper in this series [1] is concerned with a more detailed analysis of complementarity in terms of component parts of the molecular structures; the research attempts to investigate partitioning of the electrostatic potential into molecular moieties and reveals in many cases a dominant charge effect. The third paper [2] examines the relative disposition of dominant ionized atoms in the ligand and site in electrostatic complementarity. Analytical expressions are derived which describe, in simple terms, the contribution from dominant charges in the interaction between ligands and proteins.…”

“…A theoretical justification for this correlation procedure is provided in the accompanying paper [2].…”

Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor

“…Therefore, it is reasonable to expect that the most occupied binding mode would correspond to the native binding mode as observed experimentally. Subsequent selection of one or more ligand-binding modes from the list of distinct docking poses were carried out on the basis of previous experimental data, known binding mode of other ligands and the electrostatic potential complementarity between the ligand and the receptor [20][21][22]25]. …”

The atom assignment problem in automated de novo drug design. 1. Transferability of molecular fragment properties

“…Electrostatic complementarity between proteins and ligands has recently been studied systematically on 24 high-resolution ligand co-crystal complexes [21][22][23]. A number of features relevant to drug design problems can be highlighted from this work.…”