整体膜蛋白可溶性功能类似物的计算设计。

Q3 Medicine
Casper A Goverde, Martin Pacesa, Nicolas Goldbach, Lars J Dornfeld, Petra E M Balbi, Sandrine Georgeon, Stéphane Rosset, Srajan Kapoor, Jagrity Choudhury, Justas Dauparas, Christian Schellhaas, Simon Kozlov, David Baker, Sergey Ovchinnikov, Alex J Vecchio, Bruno E Correia
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引用次数: 0

摘要

仅利用计算手段重新设计复杂的蛋白质折叠仍然是一项重大挑战。在这里,我们使用强大的深度学习管道来设计复杂的折叠和整体膜蛋白的可溶性类似物。独特的膜拓扑结构(如来自 GPCR 的拓扑结构)在可溶性蛋白质组中找不到,我们证明了它们的结构特征可以在溶液中重现。生物物理分析表明,这些设计具有很高的热稳定性,而实验结构则显示出显著的设计准确性。可溶性类似物具有本地结构基团的功能,是将膜蛋白功能引入可溶性蛋白质组的概念验证,有可能为药物发现提供新方法。总之,我们设计了复杂的蛋白质拓扑结构,并用膜蛋白的功能丰富了这些拓扑结构,实验成功率很高,从而事实上扩大了功能性可溶性折叠空间。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Computational design of soluble functional analogues of integral membrane proteins.

De novo design of complex protein folds using solely computational means remains a significant challenge. Here, we use a robust deep learning pipeline to design complex folds and soluble analogues of integral membrane proteins. Unique membrane topologies, such as those from GPCRs, are not found in the soluble proteome and we demonstrate that their structural features can be recapitulated in solution. Biophysical analyses reveal high thermal stability of the designs and experimental structures show remarkable design accuracy. The soluble analogues were functionalized with native structural motifs, standing as a proof-of-concept for bringing membrane protein functions to the soluble proteome, potentially enabling new approaches in drug discovery. In summary, we designed complex protein topologies and enriched them with functionalities from membrane proteins, with high experimental success rates, leading to a de facto expansion of the functional soluble fold space.

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来源期刊
Voprosy Detskoi Dietologii
Voprosy Detskoi Dietologii Medicine-Pediatrics, Perinatology and Child Health
CiteScore
1.20
自引率
0.00%
发文量
17
期刊介绍: The scientific journal Voprosy Detskoi Dietologii is included in the Scopus database. Publisher country is RU. The main subject areas of published articles are Food Science, Pediatrics, Perinatology, and Child Health, Nutrition and Dietetics, Клиническая медицина.
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