Prediction of solution phase association constants by mapping contact points in intermolecular complexes

Atomic surface site interaction points (AIP) provide a complete description of the non-covalent interactions that one molecule can make with another. The surface site interaction model for the properties of liquids at equilibrium (SSIMPLE) algorithm can be used to calculate the free energy change associated with the pairwise interaction between two AIPs on two different molecules in any solvent. Summing these pairwise AIP interactions across an intermolecular interface that involves multiple interacting sites can be used to calculate solution phase binding free energies and association constants. A computational tool that converts the three-dimensional structure of a complex into a set of AIP contacts has been developed along with a visualisation tool to display AIP interaction maps, allowing straightforward identification of the key intermolecular contacts that contribute most to the overall binding free energy in a complex. The method successfully reproduces solution phase association constants (to within an order of magnitude) for a range of host-guest complexes involving H-bonding, aromatic and hydrophobic interactions, but performs less well for halogen-bonds and complexes involving interactions between the extended π-surfaces of fullerene-type compounds.