期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 133, 期 46, 页码 18750-18759出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja205609c
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资金
- UMDNJ Foundation
- NSF [MCB-0940187]
- NIH [MCB-0920448, P41 GM-66354]
- NIH National Center for Research Resources [NIH 5G12 RR03060]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [0920448] Funding Source: National Science Foundation
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 alpha-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 alpha-helix C-terminus and throughout the protein.
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