Calculations of Molecular Surface Area Changes with Docking of Host and Guest and Applications to Cyclodextrin Inclusion

A method for calculations of molecular surface area changes with the docking of host and guest is developed and applied to the estimation of the structures and binding constants of cyclodextrin inclusion systems. Each molecule of the host and guest is regarded to consist of hydrophilic and hydrophobic groups. The change Δ S in water-accessible surface area with the docking of these host and guest molecules is divided into four terms: Δ S oo(HG), Δ S ow(HG), Δ S wo(HG), and Δ S ww(HG). For instance, Δ S oo(HG) stands for the change in host hydrophobic surface area by overlapping with guest hydrophobic surface area. When a guest molecule is moved along the symmetry axis of cyclodextrin, the structure of the complex having the maximum Δ S oo(HG) value is close to its crystal structure. Thus, we can estimate the “solution” structure of the complex from the maximum Δ S oo(HG) value. Using this method, we predict the solution structures of six cyclodextrin inclusion systems. Furthermore, we find that the logarithm of the 1:1 binding constant is linear with the maximum Δ S oo(HG) value for 11 systems including α-, β-, and γ-cyclodextrins and aliphatic and aromatic guest molecules. The present results would be applied to other cyclodextrin inclusion systems and protein−ligand systems.