Electrostatic complementarity at ligand binding sites: Application to chorismate mutase

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 improvement exist throughout the ligand, one significant under-compensated interaction stands out. The C10 carboxylate pays substantial desolvation penalty upon binding but does not recover strong hydrogen-bonded interactions with the enzyme in the available crystal structure. Calculations suggest that replacement with a virtually isosteric nitro group may improve the electrostatic contribution to the binding free energy by 2-3 kcal/mol. The principal mechanism is a decrease in the desolvation penalty of the ligand with a smaller loss in ligand-enzyme interactions. This work shows that charge optimization techniques are capable of identifying chemically reasonable substitutions to known ligands that product substantial improvements in computed binding affinity through electrostatic enhancement. Comparison of the results across twelve independently refined active sites confirms that the approach is not overly sensitive to subtle structural variation.