美国华盛顿大学David Baker研究小组取得新进展。他们让平民科学家能够从头设计蛋白质。 相关论文发表在2019年出版的《自然》杂志上。

课题组人员在一款在线蛋白质折叠游戏-Foldit中提出了重新设计全新蛋白质的挑战。游戏向玩家展示一个完全延伸的肽链，要求他们设计出一个折叠后的蛋白结构，并获得编码该结构的氨基酸序列。经过将玩家的设计进行多次迭代计算，分析得分最高的解和进一步进行游戏优化，Foldit玩家就可以在电脑中从一个扩展的多肽链生成一系列不同的蛋白质结构及其编码序列。研究者在合成基因里编码了146个Foldit玩家设计的蛋白质，这些蛋白质序列都与自然存在的蛋白质无关。研究者发现其中有56个能够在大肠杆菌中可溶性表达，并在溶液中获得稳定的单体折叠结构。这些结构的多样性在从头设计的蛋白质中是前所未有的，代表了20个不同的折叠，包括一个在天然蛋白质中没有观察到的新折叠。作者确定了其中4个玩家设计的高分辨率蛋白质结构，发现其与游戏模型几乎相同。这项工作明确了许多成功获得新蛋白质设计过程中做出贡献的隐性知识，表明平民科学家可以发现新的创造性的解决方案，以解决突出的科学挑战，如蛋白质设计问题。

据介绍，在线平民科学项目GalaxyZoo、Eyewire和Phylo等，在数据收集、注释和处理方面取得了巨大的成功。然而在很大程度上，它们利用的是人类的模式识别技能，而不是人类的创造力。游戏《EteRNA》是个例外，游戏玩家通过探索离散二维空间内WatsonCrick碱基配对概率来学习构建新的RNA结构。然而，构建新的蛋白质在游戏中是一项更具挑战性的任务，因为蛋白质的结构需要在三维空间上进行展示和评估。

附：英文原文

Title: De novo protein design by citizen scientists

Author: Brian Koepnick, Jeff Flatten, Tamir Husain, Alex Ford, Daniel-Adriano Silva, Matthew J. Bick, Aaron Bauer, Gaohua Liu, Yojiro Ishida, Alexander Boykov, Roger D. Estep, Susan Kleinfelter, Toke Nrgrd-Solano, Linda Wei, Foldit Players, Gaetano T. Montelione, Frank DiMaio, Zoran Popovi, Firas Khatib, Seth Cooper, David Baker

Issue&Volume: Volume 570 Issue 7761, 20 June 2019

Abstract: Online citizen science projects such as GalaxyZoo, Eyewire and Phylo have proven very successful for data collection, annotation and processing, but for the most part have harnessed human pattern-recognition skills rather than human creativity. An exception is the game EteRNA, in which game players learn to build new RNA structures by exploring the discrete two-dimensional space of WatsonCrick base pairing possibilities. Building new proteins, however, is a more challenging task to present in a game, as both the representation and evaluation of a protein structure are intrinsically three-dimensional. We posed the challenge of de novo protein design in the online protein-folding game Foldit. Players were presented with a fully extended peptide chain and challenged to craft a folded protein structure and an amino acid sequence encoding that structure. After many iterations of player design, analysis of the top-scoring solutions and subsequent game improvement, Foldit players can nowstarting from an extended polypeptide chaingenerate a diversity of protein structures and sequences that encode them in silico. One hundred forty-six Foldit player designs with sequences unrelated to naturally occurring proteins were encoded in synthetic genes; 56 were found to be expressed and soluble in Escherichia coli, and to adopt stable monomeric folded structures in solution. The diversity of these structures is unprecedented in de novo protein design, representing 20 different foldsincluding a new fold not observed in natural proteins. High-resolution structures were determined for four of the designs, and are nearly identical to the player models. This work makes explicit the considerable implicit knowledge that contributes to success in de novo protein design, and shows that citizen scientists can discover creative new solutions to outstanding scientific challenges such as the protein design problem.

DOI: 10.1038/s41586-019-1274-4

Source:https://www.nature.com/articles/s41586-019-1274-4