Binding free energy calculations for P450cam-substrate complexes

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