Journal of Computer Aided Molecular Design Revision submitted July 08 Page 1 of 16 Interaction force diagrams: New insight into ligand-receptor binding

A method is described to calculate and visualize the interaction forces of ligand-receptor complexes. Starting from an X-ray crystallographic structure, a “thawing ” procedure results in a force-field energy-minimized geometry which is close to the crystallographic starting point. By subtracting non-bonded interactions of the ligand with each amino acid residue and using the resulting force vectors to describe the slope of the remaining potential, two types of interaction force diagrams are created; the first shows the direction of the force vectors in 3D and the second shows the magnitude of the force vectors. The latter representation leads to definition of an “Interaction Force Fingerprint ” (IFFP) which is characteristic of the ligand-receptor binding. IFFPs are used to discuss ligand binding in the human estrogen receptors ERα and ERβ, and provide new insight into ligand selectivity between receptor isoforms