SIMULATION OF PROTEIN UNFOLDING AND FOLDING

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The long-term aim of this project is to fold small proteins by extending the methods for simulation that Dr. Levitt developed over the past 30 years. He also plans to use information on known protein structures. The proposed research involves a variety of different theoretical and computational methods in a collaboration with an experimentalist with whom he has had a longstanding relationship. Five specific aims are to be achieved by answering these questions in the affirmative: 1. Can the aggregation of small nonpolar solutes in water be quantified in terms of hydrophobic free-energy and its dependence on contact area? He will use molecular dynamics to simulate different concentrations of nonpolar molecules in water and determine the energetics of cluster formation. 2. Can b-hairpin and a-helix folding units be unfolded and refolded? Recent studies by his collaborator, Dr. Eaton, show that the C-terminal b-hairpin of protein G refolds on a microsecond time-scale. He will simulate this using his very efficient methods, which include explicit waters. 3. Can one generate nonnative decoy structures of proteins, which are so well-packed that they look like real native structure? Dr. Levitt will draw on his work with lattice and off-lattice models, side- chain modeling and energy refinement to generate tens of thousands of all-atom structures for small protein sequences. 4. Can energy functions derived from selected sets of protein structures correctly distinguish near-native structures from decoys? He will optimize these knowledge-based energy functions by testing them on his existing decoy sets and then improving decoy generation to make discrimination more difficult. 5. Can one fold some small proteins using just the amino acid sequence? He will combine predicted secondary structures with decoy generation and knowledge-based potentials in attempts to correctly predict folded structures before they are solved experimentally.