C‐H…O hydrogen bonds in FK506‐binding protein–ligand interactions

Abstract

Hydrogen bonds are important interaction forces observed in protein structures. They can be classified as stronger or weaker depending on their energy, thereby reflecting on the type of donor. The contribution of weak hydrogen bonds is deemed as an important factor toward structure stability along with the stronger bonds. One such bond, the C-H…O type hydrogen bond, is shown to make a contribution in maintaining three dimensional structures of proteins. Apart from their presence within protein structures, the role of these bonds in protein-ligand interactions is also noteworthy. In this study, we present a statistical analysis on the presence of C-H…O hydrogen bonds observed between FKBPs and their cognate ligands. The FK506-binding proteins (FKBPs) carry peptidyl cis-trans isomerase activity apart from the immunosuppressive property by binding to the immunosuppressive drugs FK506 or rapamycin. Because the active site of FKBPs is lined up by many hydrophobic residues, we speculated that the prevalence of C-H…O hydrogen bonds will be considerable. In a total of 25 structures analyzed, a higher frequency of C-H…O hydrogen bonds is observed in comparison with the stronger hydrogen bonds. These C-H…O hydrogen bonds are dominated by a highly conserved donor, the C(α/β) of Val55 and an acceptor, the backbone oxygen of Glu54. Both these residues are positioned in the β4-α1 loop, whereas the other residues Tyr26, Phe36 and Phe99 with higher frequencies are lined up at the opposite face of the active site. These preferences could be implicated in FKBP pharmacophore models toward enhancing the ligand affinity. This study could be a prelude to studying other proteins with hydrophobic pockets to gain better insights into ligand recognition.