Localization and quantification of hydrophobicity: The molecular free energy density (MolFESD) concept and its application to sweetness recognition

A method for the localization, the quantification, and the analysis of hydr ophobicity of a molecule or a molecular fragment is presented. It is shown that the free energy of solvation for a molecule or the transfer free energ y from one solvent to another can be represented by a surface integral of a scalar quantity, the molecular free energy surface density (MolFESD), over the solvent accessible surface of that molecule. This MolFESD concept is b ased on a model approach where the solvent molecules are considered to be s mall in comparison to the solute molecule, and the solvent can be represent ed by a continuous medium with a given dielectric constant. The transfer en ergy surface density for a 1-octanol/water system is empirically determined employing a set of atomic increment contributions and distance dependent m embership functions measuring the contribution of the increments to the sur face value of the MolFESD. The MolFESD concept can be well used for the qua ntification of the purely hydrophobic contribution to the binding constants of molecule-receptor complexes. This is demonstrated with the sweeteners s ucrose and sucralose and various halogen derivatives. Therein the relative sweetness, which is assumed to be proportional to the binding constant, nic ely correlates to the surface integral over the positive, hydrophobic part of the MolFESD, indicating that the sweetness receptor can be characterized by a highly flexible hydrophobic pocket instead of a localized binding sit e.