| Restricted dead-end elimination: protein redesign with a bounded number of residue mutations. | |
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MedLine Citation:
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PMID: 19885869 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Dead-end elimination (DEE) has emerged as a powerful structure-based, conformational search technique enabling computational protein redesign. Given a protein with n mutable residues, the DEE criteria guide the search toward identifying the sequence of amino acids with the global minimum energy conformation (GMEC). This approach does not restrict the number of permitted mutations and allows the identified GMEC to differ from the original sequence in up to n residues. In practice, redesigns containing a large number of mutations are often problematic when taken into the wet-lab for creation via site-directed mutagenesis. The large number of point mutations required for the redesigns makes the process difficult, and increases the risk of major unpredicted and undesirable conformational changes. Preselecting a limited subset of mutable residues is not a satisfactory solution because it is unclear how to select this set before the search has been performed. Therefore, the ideal approach is what we define as the kappa-restricted redesign problem in which any kappa of the n residues are allowed to mutate. We introduce restricted dead-end elimination (rDEE) as a solution of choice to efficiently identify the GMEC of the restricted redesign (the kappaGMEC). Whereas existing approaches require n-choose-kappa individual runs to identify the kappaGMEC, the rDEE criteria can perform the redesign in a single search. We derive a number of extensions to rDEE and present a restricted form of the A* conformation search. We also demonstrate a 10-fold speed-up of rDEE over traditional DEE approaches on three different experimental systems. |
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Authors:
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Maria Safi; Ryan H Lilien |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of computational chemistry Volume: 31 ISSN: 1096-987X ISO Abbreviation: J Comput Chem Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-03-18 Completed Date: 2010-06-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9878362 Medline TA: J Comput Chem Country: United States |
Other Details:
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Languages: eng Pagination: 1207-15 Citation Subset: IM |
Copyright Information:
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2009 Wiley Periodicals, Inc. |
Affiliation:
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Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Algorithms Amino Acid Sequence / genetics* Models, Chemical* Mutagenesis, Site-Directed Point Mutation* Protein Conformation Proteins / chemistry*, genetics* Thermodynamics |
| Chemical | |
Reg. No./Substance:
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0/Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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