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 work focuses, therefore, on the research on enzyme–inhibitor interactions using two highly homologous enzymes as our models: β-factor XIIa and trypsin. This study so far has focused on the following: (1) arginine–carboxylate interactions such as the one occurring in the “binding pocket” of β-factor XIIa with an inhibitor; according to the present calculations, the neutral form is usually more stable than is the zwitterion in hydrophobic environments as in the case of the above-mentioned complex. (2) Interactions present in the contact region between trypsin and PTI; the contribution of some amino acids of that region to the binding energy of the complex trypsin–PTI was determined using free-energy simulation methods. (3) Interactions involved in the inhibition of trypsin by PTI; hybrid quantum-classical mechanical calculations (LSCF) were performed to further this point.