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 interactions between several leucine aminopeptidase inhibitors and various constituents of the enzyme active site has been performed using a direct 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 inhibitors, indicating that the more advanced the quantum-chemical method and, the larger the active-site model, the better is the correlation between calculated and measured binding energies. The electrostatic multipole term constitutes the dominant contribution in the total interaction energy, whereas Zn2+488 and Lys+262 enzyme residues play the crucial role in the binding of these inhibitors by leucine aminopeptidase.