Computational design of thermostabilizing D-amino acid substitutions.
J Am Chem Soc
; 133(46): 18750-9, 2011 Nov 23.
Article
em En
| MEDLINE
| ID: mdl-21978298
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Simulação de Dinâmica Molecular
/
Aminoácidos
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos