Modeling Correlated Protein Main-chain Motions in Proteins and their Ligands

Leslie A. Kuhn(1), Maria I. Zavodszky(1), Sameer Arora(2), Ming Lei(3), and
Michael F. Thorpe(4)

(1) Department of Biochemistry & Molecular Biology and Center for Biological Modeling, Michigan State University, 502C Biochemistry Building, East Lansing, MI 48824-1319; http://www.bch.msu.edu/labs/kuhn (2) Departments of Biochemistry & Molecular Biology and Computer Science & Engineering, Michigan State University, (3)Department of Biochemistry, Brandeis University, and (4)Physics & Astronomy Department, Arizona State University
 
 

We describe a new method for modeling protein and ligand main-chain flexibility in docking. The goal is to sample the full conformational space, including conformations not yet observed by crystallography, MD, or NMR. Flexibility analysis is performed using the graph-theoretic algorithm FIRST, which identifies coupled networks of covalent and non-covalent bonds within the protein. ROCK then explores available conformations by only sampling dihedral angles that preserve the coupled bond network in the protein. A representative set of protein conformations can then be used as targets for docking with SLIDE, which models protein and ligand side-chain flexibility. This combined approach for incorporating main-chain flexibility in docking is illustrated for cyclophilin A-cyclosporin and estrogen receptor-zearalenol complexes. Very recent results show that the maintenance of correlated motions between hydrogen-bonded and hydrophobic side chains is also a key aspect of ligand recognition across diverse protein-ligand complexes.