Computational Design of Thermostabilizing D-amino Acid Substitutions

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2011 Oct 8

PMID 21978298

Citations 17

Authors

Agustina Rodriguez-Granillo

Srinivas Annavarapu

Lei Zhang

Ronald L Koder

Vikas Nanda

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Rational design of the genetic code expansion toolkit for encoding of D-amino acids.

Jiang H, Weng J, Wang Y, Tsou J, Chen P, Ko A Front Genet. 2023; 14:1277489.

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Analysis of folded structure and folding thermodynamics in heterogeneous-backbone proteomimetics.

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