Electrostatic Complementarity at Ligand Binding Sites: Application to Chorismate Mutase

Abstract

Charge optimization methods facilitate examination and, potentially, improvement of electrostatic interactions between binding partners. Here charge optimization was applied to the chorismate mutase from Bacillus subtilis binding an endo-oxabicyclic transition-state analogue. Electrostatically optimized templates based on calculations using the X-ray crystal structure were used to define regions of the transition-state analogue whose electrostatic properties are sub-optimal for binding. Variants of the analogue that could exhibit improved electrostatic affinity for the enzyme were considered that more closely mimicked the optimal charge distributions. Results indicate that the transition-state analogue is remarkably complementary to the enzyme active site in terms of electrostatics throughout much of the binding site. Particularly good electrostatic complementarity is exhibited for most of the groups on the analogue that make hydrogen bonds with the enzyme. While some small potential opportunities for imp...