| Computational design of thermostabilizing D-amino acid substitutions. | |
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MedLine Citation:
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PMID: 21978298 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Judicious incorporation of D-amino acids in engineered proteins confers many advantages such as preventing degradation by endogenous proteases and promoting novel structures and functions not accessible to homochiral polypeptides. Glycine to D-alanine substitutions at the carboxy termini can stabilize α-helices by reducing conformational entropy. Beyond alanine, we propose additional side chain effects on the degree of stabilization conferred by D-amino acid substitutions. A detailed, molecular understanding of backbone and side chain interactions is important for developing rational, broadly applicable strategies in using D-amino acids to increase protein thermostability. Insight from structural bioinformatics combined with computational protein design can successfully guide the selection of stabilizing D-amino acid mutations. Substituting a key glycine in the Trp-cage miniprotein with D-Gln dramatically stabilizes the fold without altering the protein backbone. Stabilities of individual substitutions can be understood in terms of the balance of intramolecular forces both at the α-helix C-terminus and throughout the protein. |
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Authors:
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Agustina Rodriguez-Granillo; Srinivas Annavarapu; Lei Zhang; Ronald L Koder; Vikas Nanda |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-10-27 |
Journal Detail:
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Title: Journal of the American Chemical Society Volume: 133 ISSN: 1520-5126 ISO Abbreviation: J. Am. Chem. Soc. Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-17 Completed Date: 2012-03-12 Revised Date: 2013-04-01 |
Medline Journal Info:
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Nlm Unique ID: 7503056 Medline TA: J Am Chem Soc Country: United States |
Other Details:
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Languages: eng Pagination: 18750-9 Citation Subset: IM |
Affiliation:
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Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey (UMDNJ) and Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Substitution Amino Acids / chemistry* Calorimetry, Differential Scanning Circular Dichroism Models, Molecular Molecular Dynamics Simulation* Temperature Thermodynamics |
| Grant Support | |
ID/Acronym/Agency:
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5G12 RR03060/RR/NCRR NIH HHS; P41 GM-66354/GM/NIGMS NIH HHS; R01 GM089949/GM/NIGMS NIH HHS; R01GM089949-01/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amino Acids |
| Comments/Corrections | |
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