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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 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.
Computational Design of Thermostabilizing d-Amino Acid Substitutions.,Rodriguez-Granillo A, Annavarapu S, Zhang L, Koder RL, Nanda V J Am Chem Soc. 2011 Nov 23;133(46):18750-9. Epub 2011 Oct 27. PMID:21978298[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑ Rodriguez-Granillo A, Annavarapu S, Zhang L, Koder RL, Nanda V. Computational Design of Thermostabilizing d-Amino Acid Substitutions. J Am Chem Soc. 2011 Nov 23;133(46):18750-9. Epub 2011 Oct 27. PMID:21978298 doi:10.1021/ja205609c
