The Stability Landscape of de novo TIM Barrels Explored by a Modular Design Approach

Romero-Romero Sergio; Costas Miguel; Manzano Daniel-Adriano SilvaKordes SinaRojas-Ortega ErendiraTapia CinthyaGuerra YaselShanmugaratnam SoorubanRodriguez-Romero AdelaBaker DavidHoecker BirteAlejandro Fernandez-Velasco D.

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The Stability Landscape of de novo TIM Barrels Explored by a Modular Design Approach

机译：The Stability Landscape of de novo TIM Barrels Explored by a Modular Design Approach

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The ability to design stable proteins with custom-made functions is a major goal in biochemistry with practical relevance for our environment and society. Understanding and manipulating protein stability provide crucial information on the molecular determinants that modulate structure and stability, and expand the applications of de novo proteins. Since the (beta/alpha)(8)-barrel or TIM-barrel fold is one of the most common functional scaffolds, in this work we designed a collection of stable de novo TIM barrels (DeNovoTIMs), using a computational fixed-backbone and modular approach based on improved hydrophobic packing of sTIM11, the first validated de novo TIM barrel, and subjected them to a thorough folding analysis. DeNovoTIMs navigate a region of the stability landscape previously uncharted by natural TIM barrels, with variations spanning 60 degrees in melting temperature and 22 kcal per mol in conformational stability throughout the designs. Significant non-additive or epistatic effects were observed when stabilizing mutations from different regions of the barrel were combined. The molecular basis of epistasis in DeNovoTIMs appears to be related to the extension of the hydrophobic cores. This study is an important step towards the fine-tuned modulation of protein stability by design. (C) 2021 The Authors. Published by Elsevier Ltd.

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《Journal of Molecular Biology》 |2021年第18期|共20页
作者
Romero-Romero Sergio; Costas Miguel; Manzano Daniel-Adriano SilvaKordes SinaRojas-Ortega ErendiraTapia CinthyaGuerra YaselShanmugaratnam SoorubanRodriguez-Romero AdelaBaker DavidHoecker BirteAlejandro Fernandez-Velasco D.;
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Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Lab Fisicoquim & Ingn Proteinas, Mexico City;

Univ Nacl Autonoma Mexico, Fac Quim, Dept Fisicoquim, Lab Biofisicoquim, Mexico City 04510, DF;

Univ Washington, Dept Biochem, Seattle, WA 98195 USAUniv Bayreuth, Dept Biochem, D-95447 Bayreuth, GermanyUniv Nacl Autonoma Mexico, Inst Quim, Mexico City 04510, DF, Mexico;

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正文语种英语
中图分类分子生物学;
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de novo protein design; protein folding and stability; stability landscape; non-additive effects; (beta/alpha)(8)-barrel;

The Stability Landscape of de novo TIM Barrels Explored by a Modular Design Approach

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