Modeling correlated protein main-chain and side-chain motions in ligand docking and screening


Leslie A. Kuhn1, Maria I. Zavodszky1, Sameer Arora2, Ming Lei3, and Michael F. Thorpe4. (1) Department of Biochemistry & Molecular Biology and Center for Biological Modeling, Michigan State University, 502C Biochemistry Building, East Lansing, MI 48824-1319, (2) Departments of Biochemistry & Molecular Biology and Computer Science & Engineering, Michigan State University, 502C Biochemistry Building, East Lansing, MI 48824-1319, (3) Department of Biochemistry, Brandeis University, Waltham, MA, (4) Physics & Astronomy Department, Arizona State University, Tempe, AZ
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.

Docking and Scoring
9:00 AM-12:20 PM, Sunday, August 22, 2004 Pennsylvania Convention Center -- 109B, Oral

Division of Computers in Chemistry

The 228th ACS National Meeting, in Philadelphia, PA, August 22-26, 2004