仅使用目标结构设计蛋白质结合蛋白，这一成果由美国华盛顿大学David Baker研究团队经过不懈努力而取得。2022年3月24日出版的《自然》杂志发表了这项成果。

研究人员提出了一种解决蛋白设计的方案，首先对蛋白质表面选定区域可能结合模式的大空间进行广泛探索，然后在最有希望的结合模式附近加强搜索。研究人员通过从头设计将蛋白质与12种不同形状和表面特性的蛋白质靶标结合，证明了其具有广泛的适用性。生物物理特性表明，所有小于65个氨基酸的结合剂是超稳定的，并且经过实验优化后，它们可与靶标蛋白以纳摩尔到皮摩尔的亲和力结合。研究人员成功解析了五种结合剂-靶标配合物的晶体结构，这五种结构都非常接近相应的计算设计模型。

近50万个计算设计和数十万个点突变体的实验数据提供了有关该方法优势、局限性以及对目前蛋白质-蛋白质相互作用理解的详细反馈，并可用于对这两种方法进行改进。该方法可对治疗和诊断应用中各种蛋白质上的感兴趣位点进行针对性设计。

研究人员表示，除了目标三维结构之外，不使用其他信息设计与目标蛋白表面特定位点结合的蛋白质仍具有挑战性。

附：英文原文

Title: Design of protein binding proteins from target structure alone

Author: Cao, Longxing, Coventry, Brian, Goreshnik, Inna, Huang, Buwei, Park, Joon Sung, Jude, Kevin M., Markovi, Iva, Kadam, Rameshwar U., Verschueren, Koen H. G., Verstraete, Kenneth, Walsh, Scott Thomas Russell, Bennett, Nathaniel, Phal, Ashish, Yang, Aerin, Kozodoy, Lisa, DeWitt, Michelle, Picton, Lora, Miller, Lauren, Strauch, Eva-Maria, DeBouver, Nicholas D., Pires, Allison, Bera, Asim K., Halabiya, Samer, Hammerson, Bradley, Yang, Wei, Bernard, Steffen, Stewart, Lance, Wilson, Ian A., Ruohola-Baker, Hannele, Schlessinger, Joseph, Lee, Sangwon, Savvides, Savvas N., Garcia, K. Christopher, Baker, David

Issue&Volume: 2022-03-24

Abstract: The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains an outstanding challenge1–5. We describe a general solution to this problem which starts with a broad exploration of the very large space of possible binding modes to a selected region of a protein surface, and then intensifies the search in the vicinity of the most promising binding modes. We demonstrate its very broad applicability by de novo design of binding proteins to 12 diverse protein targets with very different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and following experimental optimization bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of five of the binder-target complexes, and all five are very close to the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvement of both. Our approach now enables targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications.

DOI: 10.1038/s41586-022-04654-9

Source: https://www.nature.com/articles/s41586-022-04654-9