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.