Synthetic Adenine Receptors: Direct Calculation of Binding Affinity and Entropy

A novel method for calculating binding free energies is applied to a series of water-soluble adenine receptors that have been characterized experimentally. The calculations use a predominant states method, “Mining Minima”, to identify and account for the low-energy conformations of the free and bound species. The CHARMM force field is used to estimate potential energies, and an adjusted form of the generalized Born/surface area model is used to estimate solvation energies as a function of conformation. The computed binding free energies agree with experiment to within 2.9 kJ/mol (0.7 kcal/mol) and reproduce observed trends across the series of receptors. Preorganization of two rotatable bonds enhances the calculated affinity of one receptor/adenine complex by −2.5 kJ/mol (−0.6 kcal/mol), and the change in translational/rotational entropy (−TΔ ) is 30 kJ/mol (7 kcal/mol). The concept of the translational/rotational entropy change upon binding in the present model is compared with others previously presente...