Impact of Inert Crowders on Host-Guest Recognition Process.

Biological environments typically contain high concentrations (300-400 mg/mL) of different macromolecules at volume fractions as large as 30%-40%. Biomolecular recognition processes, a ubiquitous biological phenomena, occurring in such crowded heterogeneous media would differ significantly compared to the dilute buffer solutions. Here we quantify the potential impact of inert crowders on prototypical host-guest recognition process by explicit-solvent molecular dynamics (MD) simulations in atomic resolution. We demonstrate that the crowders, when smaller in size, would facilitate the binding process of the guest molecule by decreasing the free energy barrier for binding via excluded volume effect and desolvation of the host receptor. However, the extent of crowder-induced stabilization of a host-guest complex is found to be significantly higher when the guest molecule is sterically constricted to approach the host along a centrosymmetric direction, compared to its unrestricted, freely diffusive movement. A kinetic analysis of the recognition process reveals that the origin of a relatively stronger crowder impact during constricted movement of guest molecule lies in the relatively enhanced residence time of the guest inside the host by crowders. Together, our results suggest that the extent of impact of crowding on recognition processes would be contingent upon the presence or absence of constriction on ligand movement.