Chemoselective intermolecular hydrogen bonding in peptides: An electronic and topological study on the H-bonding selectivities in peptidomimetic HCV protease inhibitor telaprevir

Abstract

Chemoselectivity in intermolecular hydrogen bonding in polypeptides is demonstrated via a comprehensive study on the H-bonding characteristics of the peptidomimetic hepatitis C protease inhibitor telaprevir (1) using well-established computational tools. Starting with a QTAIM and NBO analysis of the H-bonding selectivities observed in the crystal structure of 1 and its 4-HBA cocrystal, the analysis was extended to model systems of the amino acid residues of 1 (P1res, P3res, and P4res) complexed with formic acid. The carboxylic acid/amide H-bonding of these models showed consistently stronger H-bonding at the P3 residue. The degree of chemoselectivity was quantified by comparing the QTAIM and NBO parameters between the P1res-FA, P3res-FA, and P4res-FA models. The chemoselectivity in 1 is consistent with the calculations of the FA residue models. These results demonstrate the impact of chemoselectivity in non-covalent interactions and can be extended to understanding H-bonding selectivities in polypeptides, proteins, and other macromolecular systems.