We apply the recently developed variational implicit-solvent model (VISM) to study hydration effects in the high-affinity binding of the guest bicyclo[2.2.2]octane (B2) derivative to the synthetic host cucurbit[7]uril (CB[7]).  The free energy of this host-guest system is determined by the minimization of the VISM free-energy functional of all possible interfaces separate the host and guest atoms from the water molecules. This free energy consists of the volume and surface energies, the solute-solvent van der Waals interaction energy, and the electrostatic solvation energy.  We use the Coulomb-field approximation (CFA) to efficiently describe the electrostatic interactions of the system.  Without electrostatics, the host cavity slightly favors the dry state over the wet state. However, the wet state becomes much more favorable when the electrostatics is included.  These results are in line with MD simulations performed in an identical system.  We also find that the attractive Coulombic interaction between CB[7] and B2 in vacuum balances the binding penalty stemming from the electrostatic part of the hydration energy, showing that the electrostatics play an important role in the host-guest binding. Our results reveal the importance of the coupling of polar and nonpolar interactions in biomolecular systems. We expect that a further refinement by implementing the Poisson-Boltzmann description instead of the CFA, the VISM can predict more quantitatively the molecular binding affinities and molecular recognition scoring functions. This is joint work with Joe Dzubiella, Bo Li, Andy McCammon, and many others.

Variational implicit-solvent modeling of host-guest systems: A case study on cucurbit[7]uril

246th National Meeting (2013)

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