Computational Design of Thermostabilizing D-Amino Acid Substitutions

Agustina Rodriguez-Granillo; Srinivas Annavarapu; Lei Zhang; Ronald L. Koder; Vikas Nanda

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Computational Design of Thermostabilizing D-Amino Acid Substitutions

机译：热稳定D-氨基酸取代的计算设计

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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 a-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 compu tational 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 a-helix C-terminus and throughout the protein.

机译：将D-氨基酸明智地掺入工程蛋白中可带来许多优势，例如防止内源蛋白酶降解以及促进同型手性多肽无法获得的新结构和功能。羧基末端的甘氨酸取代D-丙氨酸可以通过减少构象熵来稳定a螺旋。除丙氨酸外，我们还提出了对D-氨基酸取代所赋予的稳定程度的附加侧链效应。对骨架和侧链相互作用的详细分子理解对于开发合理的，广泛使用的使用D-氨基酸提高蛋白质热稳定性的策略非常重要。结构生物信息学与计算蛋白质设计相结合的洞察力可以成功指导稳定D-氨基酸突变的选择。用D-Gln取代Trp笼子微蛋白中的关键甘氨酸可显着稳定折叠，而不会改变蛋白骨架。可以根据α-螺旋C-末端和整个蛋白质的分子内力平衡来理解单个取代的稳定性。

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《Journal of the American Chemical Society》 |2011年第46期|p.18750-18759|共10页
作者
Agustina Rodriguez-Granillo; Srinivas Annavarapu; Lei Zhang; Ronald L. Koder; Vikas Nanda;
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作者单位

Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey (UMDNJ) and Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854, United States;

Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey (UMDNJ) and Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854, United States;

Department of Physics, The City College of New York, New York, New York 10031, United States;

Department of Physics, The City College of New York, New York, New York 10031, United States;

Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey (UMDNJ) and Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854, United States;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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Computational Design of Thermostabilizing D-Amino Acid Substitutions

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