Modeling enzyme-inhibitor interactions in serine proteases

We are interested in modeling enzyme-inhibitor interactions with a view to improve the understanding of the biology of these processes. The present wo rk focuses, therefore, on the research on enzyme-inhibitor interactions usi ng two highly homologous enzymes as our models: beta-factor XIIa and trypsi n. This study so far has focused on the following: (1) arginine-carboxylate interactions such as the one occurring in the "binding pocket" of beta-fac tor XIIa with an inhibitor; according to the present calculations, the neut ral form is usually more stable than is the zwitterion in hydrophobic envir onments as in the case of the above-mentioned complex. (2) Interactions pre sent in the contact region between trypsin and PTI; the contribution of som e amino acids of that region to the binding energy of the complex trypsin-P TI was determined using free-energy simulation methods. (3) Interactions in volved in the inhibition of trypsin by PTI; hybrid quantum-classical mechan ical calculations (LSCF) were performed to further this point. (C) 1994 Joh n Wiley & Sons, Inc.