CALCULATION OF LIGAND-BINDING FREE-ENERGIES FROM MOLECULAR-DYNAMICS SIMULATIONS

A recently developed method for predicting binding affinities in ligan d-receptor complexes, based on interaction energy averaging and confor mational sampling by molecular dynamics simulation, is presented. Pola r and nonpolar contributions to the binding free energy are approximat ed by a Linear scaling of the corresponding terms in the average inter molecular interaction energy for the bound and free states of the liga nd. While the method originally assumed the validity of electrostatic linear response, we show that incorporation of systematic deviations f rom Linear response derived from free energy perturbation calculations enhances the accuracy of the approach. The method is applied to compl exes of wild-type and mutant human dihydrofolate reductases with 2,4-d iaminopteridine and 2,4-diaminoquinazoline inhibitors. It is shown tha t a binding energy accuracy of about 1 kcal/mol is attainable even for multiply ionized compounds, such as methotrexate, for which electrost atic interactions energies are very large. (C) 1998 John Wiley & Sons, Inc.