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 dockin g of host and guests developed and applied to the estimation of the structu res 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 Delta S in water-accessible surface area with the docki ng of these host and guest molecules is divided into four terms: Delta Soo( HG), Delta Sow(HG), Delta Swo(HG), and Delta Sww(HG). For instance, Delta S oo(HG) stands for the change in host hydrophobic surface area by overlappin g 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 Delta Soo(HG) value is close to its crystal structure. Thus, we ca n estimate the '"solution" structure of the complex from the maximum Delta Soo(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 Delta Soo(HC) value fo r 11 systems including alpha-, beta-, and gamma-cyclodextrins and aliphatic and aromatic guest molecules. The present results would be applied to othe r cyclodextrin inclusion systems and protein-ligand systems.