Binding free energy calculations for P450cam-substrate complexes.

Abstract

A recently proposed semi-empirical method for calculating binding free energies was used to examine the binding of a variety of substrates to cytochrome P450cam. For a set of 11 different potential substrates of cytochrome P450cam, both the absolute and relative binding free energies were generally well reproduced. The mean error in the calculated absolute binding free energy for all 11 compounds is 0.55 kcal/mol. Forty-eight out of 55 calculated relative binding free energies have the correct sign and the mean unsigned error between calculated and experimental relative binding free energies is 0.77 kcal/mol. For one substrate, thiocamphor, the effect of substrate orientation on the calculated binding free energy was examined. The ability of this method to predict the effect of active site mutations was also examined in two cases.