Non-empirical analysis of the nature of the inhibitor-active-site interactions in leucine aminopeptidase

Non-empirical analysis of the physical nature of the intermolecular interac tions between several leucine aminopeptidase inhibitors and various constit uents of the enzyme active site has been performed using a diner version of the hybrid variation-perturbation decomposition of SCF and MP2 interaction energies. The interaction energy terms obtained at different theory levels have been correlated with experimentally measured activities of the inhibi tors, indicating that the more advanced the quantum-chemical method and, th e larger the active-site model, the better is the correlation between calcu lated and measured binding energies. The electrostatic multipole term const itutes the dominant contribution in the total interaction energy, whereas Z n(2+)488 and Lys(2+)262 enzyme residues play the crucial role in the bindin g of these inhibitors by leucine aminopeptidase. (C) 1999 Elsevier Science B.V. All rights reserved.