2015/02/16

Modulating Weak Interactions for Molecular Recognition: A Dynamic Combinatorial Analysis for Assessing the Contribution of Electrostatics to the Stability of CH-pi Bonds in Water

The interactions between aromatic moieties and aliphatic entities are of paramount importance for essential molecular recognition events. In particular, CH-pi contacts are present in a variety of biomolecular complexes, and provide the impetus for different binding processes, including the recognition of glycans by proteins. Within a scientific collaboration leaded by CIB-CSIC (Asensio), with research groups at Logroño (Corzana), and Los Angeles (Jiménez-Oses), the group of J. Jiménez-Barbero at the Infectious Disease Programme at CIC bioGUNE has contributed to understand the role of electrostatic and charge-transfer contributions to stabilize CH-pi complexes in water solution, by attaching electron-withdrawing substituents to the interacting carbon atom.
Using a multidisciplinary approach that combined dynamic combinatorial chemistry methods, NMR techniques, and theoretical calculations, they have demonstrated that CH polarization in water largely stabilizes the CH-pi contacts exacerbated by the hydrophobic "solvent cage" effect, thus proving that electrostatics and charge transfer forces are remarkably relevant.
This work has provided an unambiguous and quantitative answer to a simple question that is of general relevance in different fields of chemistry and biology.
Also, from a drug design perspective, it has been shown that the attachment of electron-withdrawing atoms to the interacting CH groups is a valid strategy to stabilize CH-pi bonds in physiological environments.