美国华盛顿大学David Baker等研究人员合作实现生物活性螺旋肽高亲和力结合分子的从头设计。相关论文于2023年12月18日在线发表在《自然》杂志上。

研究人员表示，许多肽类激素在与受体结合后会形成一个α-螺旋，对它们的灵敏检测方法有助于更好地进行临床疾病管理。现在，全新蛋白质设计可以产生对结构蛋白质具有高亲和力和特异性的结合分子。然而，如何设计蛋白质与具有螺旋倾向的短肽之间的相互作用是一个尚未解决的难题。

研究人员介绍了参数生成和基于深度学习的蛋白质设计方法，以应对这一挑战。研究表明，通过扩展RFdiffusion，可以为灵活的靶标设计结合分子，并通过连续噪声和去噪（部分扩散）来完善输入结构模型，无论是完善其他方法生成的设计，还是完全从随机噪声分布出发，都可以为螺旋肽靶标生成皮摩尔亲和力结合分子。据研究人员所知，这是针对任何蛋白质或小分子靶标直接通过计算生成的亲和力最高的设计结合蛋白，无需任何实验优化。

RFdiffusion设计能够富集甲状旁腺激素和胰高血糖素，并随后通过质谱法进行检测，还能构建基于生物发光的蛋白质生物传感器。为构象可变的目标设计结合剂，并通过部分扩散优化天然和设计的蛋白质，这种能力应该具有广泛的用途。

附：英文原文

Title: De novo design of high-affinity binders of bioactive helical peptides

Author: Torres, Susana Vzquez, Leung, Philip J. Y., Venkatesh, Preetham, Lutz, Isaac D., Hink, Fabian, Huynh, Huu-Hien, Becker, Jessica, Yeh, Andy Hsien-Wei, Juergens, David, Bennett, Nathaniel R., Hoofnagle, Andrew N., Huang, Eric, MacCoss, Michael J., Expsit, Marc, Lee, Gyu Rie, Bera, Asim K., Kang, Alex, De La Cruz, Joshmyn, Levine, Paul M., Li, Xinting, Lamb, Mila, Gerben, Stacey R., Murray, Analisa, Heine, Piper, Korkmaz, Elif Nihal, Nivala, Jeff, Stewart, Lance, Watson, Joseph L., Rogers, Joseph M., Baker, David

Issue&Volume: 2023-12-18

Abstract: Many peptide hormones form an alpha-helix upon binding their receptors1–4, and sensitive detection methods for them could contribute to better clinical management of disease5. De novo protein design can now generate binders with high affinity and specificity to structured proteins6,7. However, the design of interactions between proteins and short peptides with helical propensity is an unmet challenge. Here, we describe parametric generation and deep learning-based methods for designing proteins to address this challenge. We show that by extending RFdiffusion8 to enable binder design to flexible targets, and to refining input structure models by successive noising and denoising (partial diffusion), picomolar affinity binders can be generated to helical peptide targets both by refining designs generated with other methods, or completely de novo starting from random noise distributions. To our knowledge these are the highest affinity designed binding proteins against any protein or small molecule target generated directly by computation without any experimental optimisation. The RFdiffusion designs enable the enrichment and subsequent detection of parathyroid hormone and glucagon by mass spectrometry, and the construction of bioluminescence-based protein biosensors. The ability to design binders to conformationally variable targets, and to optimise by partial diffusion both natural and designed proteins, should be broadly useful.

DOI: 10.1038/s41586-023-06953-1

Source: https://www.nature.com/articles/s41586-023-06953-1