Document Detail


Computational design of thermostabilizing D-amino acid substitutions.
MedLine Citation:
PMID:  21978298     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Agustina Rodriguez-Granillo; Srinivas Annavarapu; Lei Zhang; Ronald L Koder; Vikas Nanda
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Publication Detail:
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:
Title:  Journal of the American Chemical Society     Volume:  133     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-17     Completed Date:  2012-03-12     Revised Date:  2013-08-23    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18750-9     Citation Subset:  IM    
Affiliation:
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.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Substitution
Amino Acids / chemistry*
Calorimetry, Differential Scanning
Circular Dichroism
Models, Molecular
Molecular Dynamics Simulation*
Temperature
Thermodynamics
Grant Support
ID/Acronym/Agency:
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:
0/Amino Acids
Comments/Corrections

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