Arene-arene interactions play important roles in protein-ligand complex formation. Here, we investigate the characteristics of arene-arene interactions between small organic molecules and aromatic amino acids in protein interiors. The study is based on X-ray crystallographic data and quantum mechanical calculations using the enzyme acetylcholinesterase and selected inhibitory ligands as a model system. It is shown that the arene substituents of the inhibitors dictate the strength of the interaction and the geometry of the resulting complexes. Importantly, the calculated interaction energies correlate well with the measured inhibitor potency. Non-hydrogen substituents strengthened all interaction types in the protein milieu, in keeping with results for benzene dimer model systems. The interaction energies were dispersion-dominated, but substituents that induced local dipole moments increased the electrostatic contribution and thus yielded more strongly bound complexes. These findings provide fundamental insights into the physical mechanisms governing arene-arene interactions in the protein milieu and thus into molecular recognition between proteins and small molecules.
Title: The Nature of Activated Non-classical Hydrogen Bonds: A Case Study on Acetylcholinesterase-Ligand Complexes Berg L, Mishra BK, Andersson CD, Ekstrom F, Linusson A Ref: Chemistry, 22:2672, 2016 : PubMed
Molecular recognition events in biological systems are driven by non-covalent interactions between interacting species. Here, we have studied hydrogen bonds of the CHY type involving electron-deficient CH donors using dispersion-corrected density functional theory (DFT) calculations applied to acetylcholinesterase-ligand complexes. The strengths of CHY interactions activated by a proximal cation were considerably strong; comparable to or greater than those of classical hydrogen bonds. Significant differences in the energetic components compared to classical hydrogen bonds and non-activated CHY interactions were observed. Comparison between DFT and molecular mechanics calculations showed that common force fields could not reproduce the interaction energy values of the studied hydrogen bonds. The presented results highlight the importance of considering CHY interactions when analysing protein-ligand complexes, call for a review of current force fields, and opens up possibilities for the development of improved design tools for drug discovery.
