Unusual bond formation in aspartic protease inhibitors:: A theoretical study

The origin of the formation of the weak bond N vertical bar center dot center dot center dot C=O involved in an original class of aspartic protease inhibitors was investigated by means of the electron localization function (ELF) and explicitly correlated wave-function (MRCI) analysis. The distance between the electrophilic C and the nucleophilic N centers appears to be controlled directly by the polarity and proticity of the medium. In light of these investigations, an unusual dative N-C bonding picture was characterized. Formation of this bond is driven by the enhancement of the ionic contribution C+-O- induced mainly by the polarization effect of the near N lone pair, and to a lesser extent by a weak charge delocalization N -> CO. Although the main role of the solvating environment is to stabilize the ionic configuration, the protic solvent can enhance the C+-O- configuration through a slight but cumulative charge transfer towards water molecules in the short N-C distance regime. Our revisited bond scheme suggests the possible tuning of the N-CO interaction in the design of specific inhibitors.