The Surprising Importance of Peptide Bond Contacts in Drug–Protein Interactions

5 years ago

The Surprising Importance of Peptide Bond Contacts in Drug–Protein Interactions

C. David Sherrill, Robert M. Parrish, Daniel L. Cheney, Doree F. Sitkoff

The study of noncovalent interactions, notably including drug–protein binding, relies heavily on the language of localized functional group contacts: hydrogen bonding, π–π interactions, CH–π contacts, halogen bonding, etc. Applying the state-of-the-art functional group symmetry-adapted perturbation theory (F-SAPT) to an important question of chloro versus methyl aryl substitution in factor Xa inhibitor drugs, we find that a localized contact model provides an incorrect picture for the origin of the enhancement of chloro-containing ligands. Instead, the enhancement is found to originate from many intermediate-range contacts distributed throughout the binding pocket, particularly including the peptide bonds in the protein backbone. The contributions from these contacts are primarily electrostatic in nature, but require ab initio computations involving nearly the full drug–protein pocket system to be accurately quantified. F-SAPT analysis is applied to elucidate the origins of binding enhancement in Cl- versus Me-containing ligands targeting the factor Xa S1-pocket. The enhancement of Cl-containing ligands is found to arise from many separate and intermediate-range contacts throughout the S1 pocket, notably including a number of significant differential electrostatic interactions with peptide bonds. This study underscores the potential of tools such as SAPT and F-SAPT to provide insights into molecular recognition that may not be wholly intuitive.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701031