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Novel Algorithms for Computational Protein Design, with Applications to Enzyme Redesign and Small-Molecule Inhibitor Design

dc.contributor.advisor Donald, Bruce R Georgiev, Ivelin Stefanov 2009-05-01T18:24:36Z 2011-07-26T04:30:03Z 2009
dc.description.abstract <p>Computational protein design aims at identifying protein mutations and conformations with desired target properties (such as increased protein stability, switch of substrate specificity, or novel function) from a vast combinatorial space of candidate solutions. The development of algorithms to efficiently and accurately solve problems in protein design has thus posed significant computational and modeling challenges. Despite the inherent hardness of protein design, a number of computational techniques have been previously developed and applied to a wide range of protein design problems. In many cases, however, the available computational protein design techniques are deficient both in computational power and modeling accuracy. Typical simplifying modeling assumptions for computational protein design are the rigidity of the protein backbone and the discretization of the protein side-chain conformations. Here, we present the derivation, proofs of correctness and complexity, implementation, and application of novel algorithms for computational protein design that, unlike previous approaches, have provably-accurate guarantees even when backbone or continuous side-chain flexibility are incorporated into the model. We also describe novel divide-and-conquer and dynamic programming algorithms for improved computational efficiency that are shown to result in speed-ups of up to several orders of magnitude as compared to previously-available techniques. Our novel algorithms are further incorporated as part of K*, a provably-accurate ensemble-based algorithm for protein-ligand binding prediction and protein design. The application of our suite of protein design algorithms to a variety of problems, including enzyme redesign and small-molecule inhibitor design, is described. Experimental validation, performed by our collaborators, of a set of our computational predictions confirms the feasibility and usefulness of our novel algorithms for computational protein design.</p>
dc.format.extent 4917326 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Computer Science
dc.subject Dead
dc.subject End Elimination
dc.subject protein flexibility
dc.subject protein
dc.subject ligand binding
dc.subject provably
dc.subject accurate algorithms
dc.subject small
dc.subject molecule inhibitors
dc.subject structure
dc.subject based protein design
dc.title Novel Algorithms for Computational Protein Design, with Applications to Enzyme Redesign and Small-Molecule Inhibitor Design
dc.type Dissertation
dc.department Computer Science
duke.embargo.months 24

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