  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.
