Solvent's Role in Cavity-Ligand Recognition Would Depend on the Mode of Ligand Diffusion.

Solvent is known to play crucial roles in dictating the thermodynamics and kinetics of the biomolecular recognition process. Here, we show that the extent of significance of water in modulating the ligand recognition process is critically contingent on the ligand diffusion and on the constraints introduced on it. Toward the end, we use a well-known prototypical system of spherical ligand diffusing freely toward a hydrophobic concave cavity in explicit water. We analyze a large series of adaptively sampled unbiased molecular dynamics simulation trajectories within the framework of time-structured independent component analysis (TICA). Our quantitative investigations reveal that water would play a significant role in the ligand recognition process, provided that the ligand is constricted to diffuse along a centro-symmetric fashion. On the contrary, water's contribution in the ligand recognition process would diminish to a negligible value if the ligand freely diffuses toward the pocket. A Markov state model (MSM) constructed using the simulated trajectories identifies a set of transiently populated metastable states comprising partially ligand-unbound macro states, alongside ligand-bound and ligand-unbound pose and gives rise to multiple transition paths of ligand in its way to the hydrophobic cavity. Lifting the restriction on ligand movement changes its binding pathway, time scales, and the extent of the role of solvent in modulating the recognition process.