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Unusual Bond Formation in Aspartic Protease Inhibitors: A Theoretical Study
Author(s) -
Pilmé Julien,
Berthoumieux Hélène,
Robert Vincent,
FleuratLessard Paul
Publication year - 2007
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200601250
Subject(s) - protease , chemistry , bond , aspartic acid , biochemistry , enzyme , business , amino acid , finance
The origin of the formation of the weak bond N|⋅⋅⋅CO 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 NC 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 NC distance regime. Our revisited bond scheme suggests the possible tuning of the NCO interaction in the design of specific inhibitors.