Water Structure, Dynamics, and Spectral Signatures: Changes Upon Model Cavity-Ligand Recognition

It is becoming increasingly evident that water plays an active role in noncovalent receptor-ligand association. In this study, hydrophobic cavity-ligand association in a model system is characterized through the analysis of the structure, dynamics, and corresponding spectral signatures of water at different stages of the binding process. Molecular dynamics simulations reveal that the reorientation of the water molecules around the ligand becomes faster as the receptor-ligand distance reduces, which is correlated with the decrease in number of water-water hydrogen bonds within the ligand hydration shells. Prompted by the need for calculating physical quantities that can be amenable to experimental validation, the changes in the spectroscopic features upon cavity-ligand binding are investigated. The analysis of both linear and nonlinear infrared spectra allows direct insight into the evolution of water structure and dynamics around the ligand. In particular, characteristic spectroscopic features emerge at key stages of the binding process, which are related to changes in the hydrogen. bond topology of water around the ligand. This study demonstrates that computer simulations and vibrational spectroscopy could be integrated to facilitate the direct study of solvent effects in biomolecular association.