PRIORITIZED ASSEMBLY IN PROTEIN CONFORMATIONAL SEARCH

An efficient and effective conformational search method is essential for solving the computational protein folding problem. Prevalent conformational search models are fast but incomplete. Proposed here is an exhaustive enumeration-based search method that combines a focus on the most promising search paths with a complete coverage of the conformational space. The search is a prioritized building-up process: Structural templates of low energy are generated for short segments of the chain. Structural elements, either templates or individual residues, are added to a growing conformation one at a time. The addition of a structural element is prioritized on its energetical contribution one at a time. The addition of structural element is prioritized on its energetical contribution to the conformation as a whole. Simple templates such as tight turns, helices or strands form packing clusters such as hairpins and beta-sheets. A finished conformation is often the assembly of packing clusters. Such efficiency is achieved by pruning provably unpromising search branches at each building-up step. Phase I will implement the architecture of prioritized assembly-based search, demonstrating the feasibility of the approach. Phase II will develop algorithms for computing tight lower bounds of conformational energy, which are crucial for effective branch-and-bound search. Phase III will develop a comprehensive conformational search program for computational protein folding: PROPOSED COMMERCIAL APPLICATION: The primary market will be the academic research labs and technology concerns that need diverse sets of possible conformations for investigating peptides, proteins and protein-protein complexes. An additional market is the research labs that need near native or misfolded protein structures (decoys) for testing and improving their energy potentials and search methods.