Interactive computer graphics modeling and molecular mechanics calculations of protein - ligand interactions

Abstract

Model complexes of porcine pancreatic elastase with the inhibitor, trifluoroacetyl-Lys-Ala-p-trifluoromethylanilide, and of bovine trypsin with the microbial inhibitor, leupeptin, were generated using interactive computer graphics. The models were refined using molecular mechanics calculations and compared to crystal structures of the complexes. In the trypsin - leupeptin study, the two differences between the best model and the crystal structure were resolved by reference to the specific environment of the complex in a crystal versus that in solution. Using the same techniques, three of the eight subsites of porcine pancreatic elastase were investigated using three series of substrates. Binding and rate constants were calculated for all substrates and compared to published kinetic data. In all the enzyme - substrate studies, modeling and molecular mechanics alone proved insufficient to reproduce the empirical kinetic constants. Corrections for differential solvation of the various complexes, entropies of transfer and entropies of restricted internal rotation were required.