Association of two biological macromolecules is a fundamental biological phenomenon and an unsolved theoretical problem.
We have optimized and applied a two-step docking procedure (pseudo-Brownian rigid body docking followed by Biased Probability Monte Carlo minimization of the ligand interacting side chains) to protein-protein docking of uncomplexed structures for the CAPRI competition [Fernandez-Recio 2004] with very good results (Figure 2). In another recent publication [Schapira 2003] we demonstrated that ensembles of the rigid-body docking solutions generated by the simulations were subsequently used to project the docking energy landscapes onto the protein surfaces. We found that highly populated low-energy regions consistently corresponded to actual binding sites. The procedure was validated on a test set of 21 known protein-protein complexes not used in the training set. As much as 81% of the predicted high-propensity patch residues were located correctly in the native interfaces. This approach can guide the design of mutations on the surfaces of proteins, provide geometrical details of a possible interaction, and help to annotate protein surfaces in structural proteomics.
Only about one third of the protein complexes can be docked without serious considerations for the induced conformational changes upon docking. Previously we successfully used side-chain refinement of the interfaces to improve the ranking of the near-native docking geometries. In 2004 we analyzed how differential geometry measures and low-resolution models can be applied to analyze the backbone flexibility and generate alternative conformations [Kovacs 2004].
Dong M, Lam PC, Pinon DI, Hosohata K, Orry A, Sexton PM, Abagyan R, Miller LJ Molecular Basis of Secretin Docking to Its Intact Receptor Using Multiple Photolabile Probes Distributed throughout the Pharmacophore. J Biol Chem, 2011 Jul 8, 286, 23888-99
Miller LJ, Chen Q, Lam PC, Pinon DI, Sexton PM, Abagyan R, Dong M. Refinement of glucagon-like peptide 1 docking to its intact receptor using mid-region photolabile probes and molecular modeling. J Biol Chem, 2011 May 6, 286, 15895-907
Wu YW, Goody RS, Abagyan R, Alexandrov K Structure of the disordered C terminus of Rab7 GTPase induced by binding to the Rab geranylgeranyl transferase catalytic complex reveals the mechanism of Rab prenylation. J Biol Chem, 2009 May 8, 284, 13185-92