Noncovalent Interaction Analysis in Fluctuating Environments

Noncovalent interactions play a central role in many chemical and biological systems. In a previous study, Johnson et al. developed a noncovalent interaction (NCI) index to characterize and visualize different types of weak interactions. To apply the NCI analysis to fluctuating environments as in the solution phase, we here developed a new averaged noncovalent interaction (i.e., aNCI) index along with a fluctuation index to characterize the magnitude of interactions and fluctuations. We applied aNCI for various systems including solute–solvent and ligand–protein noncovalent interactions. For water and benzene molecules in aqueous solution, solvation structures and the specific hydrogen bond patterns were visualized clearly. For the Cl– + CH3Cl SN2 reaction in aqueous solution, charge reorganization influences over solvation structure along SN2 reaction were revealed. For ligand–protein systems, aNCI can recover several key fluctuating hydrogen bond patterns that have potential applications for drug design. Therefore, aNCI, as a complementary approach to the original NCI method, can extract and visualize noncovalent interactions from thermal noise in fluctuating environments.