On the Role of Solvent in Hydrophobic Cavity-ligand Recognition Kinetics

Abstract: Solvent often manifests itself as the key determinant of the kinetic aspect of molecular recognition process. While the solvent is often depicted as a source of barrier in the ligand recognition process by polar cavity, the nature of solvent's role in the recognition process involving hydrophobic cavity and hydrophobic ligand remains to be addressed. In this work, we quantitatively assess the role of solvent in dictating the kinetic process of recognition in a popular system involving hydrophobic cavity and ligand. In this prototypical system the hydrophobic cavity undergoes \textit{dewetting transition} as the ligand approaches the cavity, which influences the cavity-ligand recognition kinetics. Here, we build Markov state model (MSM) using adaptively sampled unrestrained molecular dynamics simulation trajectories to map the kinetic recognition process. The MSM-reconstructed free energy surface recovers a broad water distribution at an intermediate cavity-ligand separation, consistent with previous report of dewetting transition in this system. Time-structured independent component analysis of the simulated trajectories quantitatively shows that cavity-solvent density contributes considerably in an optimised reaction coordinate involving cavity-ligand separation and water occupancy. Our approach quantifies two solvent-mediated macro states at an intermediate separation of the cavity-ligand recognition pathways, apart from the fully ligand-bound and fully ligand-unbound macro states. Interestingly, we find that these water-mediated intermediates, while transient in populations, can undergo slow mutual interconversion and create possibilities of multiple pathways of cavity recognition by the ligand. Overall, the work provides a quantitative assessment of the role that solvent plays in facilitating the recognition process involving hydrophobic cavity.