Variational Implicit-Solvent Modeling of Host-Guest Binding: A Case Study on Cucurbit[7]urill

The synthetic host cucurbit[7]uril (CB[7]) binds aromatic guests or metal complexes with ultrahigh affinity compared with that typically displayed in protein- ligand binding. Due to its small size, CB[7] serves as an ideal receptor-ligand system for developing computational methods for molecular recognition. Here, we apply the recently developed variational implicit-solvent model (VISM), numerically evaluated by the level-set method, to study hydration effects in the high-affinity binding of the B2 bicyclo[2.2.2]-octane derivative to CB[7]. For the unbound host, we find that the host cavity favors the hydrated state over the dry state due to electrostatic effects. For the guest binding, we find reasonable agreement to experimental binding affinities. Dissection of the individual VISM free-energy contributions shows that the major driving forces are water-mediated hydrophobic interactions and the intrinsic (vacuum) host-guest van der Waals interactions. These findings are in line with recent experiments and molecular dynamics simulations with explicit solvent. It is expected that the level-set VISM, with further refinement on the electrostatic descriptions, can efficiently predict molecular binding and recognition in a wide range of future applications.