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Computational design of thermostabilizing D-amino acid substitutions.


ABSTRACT: 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 ?-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 ?-helix C-terminus and throughout the protein.

SUBMITTER: Rodriguez-Granillo A 

PROVIDER: S-EPMC3443866 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Computational design of thermostabilizing D-amino acid substitutions.

Rodriguez-Granillo Agustina A   Annavarapu Srinivas S   Zhang Lei L   Koder Ronald L RL   Nanda Vikas V  

Journal of the American Chemical Society 20111027 46


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  ...[more]

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