Refinement of docked protein-ligand and protein-DNA structures using low frequency normal mode amplitude optimization

Prediction of structural changes resulting from complex formation, both in ligands and receptors, is an important and unsolved problem in structural biology. In this work, we use all-atom normal modes calculated with the Elastic Network Model as a basis set to model structural flexibility during formation of macromolecular complexes and refine the non-bonded intermolecular energy between the two partners (protein-ligand or protein-DNA) along 5-10 of the lowest frequency normal mode directions. The method handles motions unrelated to the docking transparently by first applying the modes that improve non-bonded energy most and optionally restraining amplitudes; in addition, the method can correct small errors in the ligand position when the first six rigid-body modes are switched on. For a test set of six protein receptors that show an open-to-close transition when binding small ligands, our refinement scheme reduces the protein coordinate cRMS by 0.3-3.2 A. For two test cases of DNA structures interacting with proteins, the program correctly refines the docked B-DNA starting form into the expected bent DNA, reducing the DNA cRMS from 8.4 to 4.8 A and from 8.7 to 5.4 A, respectively. A public web server implementation of the refinement method is available at http://lorentz.immstr.pasteur.fr.