用Raygun实现天然蛋白质的小型化和修饰
用Raygun实现天然蛋白质的小型化和修饰
作者： 小柯机器人 发布时间：2026/8/3 13:34:14
本期文章：《自然》：Online/在线发表
美国杜克大学Rohit Singh课题组取得一项新突破。他们揭示了用Raygun实现天然蛋白质的小型化和修饰。2026年7月29日，国际知名学术期刊《自然》发表了这一成果。
在这里，该团队介绍了Raygun，这是一个生成式人工智能框架，可以实现蛋白质的小型化、修改和增强，主题是由语言模型嵌入构建的蛋白质序列的概率编码。他们的关键概念进步是将每个蛋白质编码为固定维度的概率分布，而不是高维空间中的可变长度序列，从而使任何长度的蛋白质都可以直接比较。仅受两个控制置换和长度变化的参数控制，Raygun可以将蛋白质缩小10-25%（有时超过50%），将其扩展到自然大小之外，并引入广泛的序列多样性，同时保持预测的结构完整性和功能位点。
在基于细胞的验证中，Raygun将荧光蛋白（2比FPbase中96%的荧光蛋白短）和TurboID（一种广泛用于蛋白质组学的合成生物素连接酶）小型化。它还扩大了表皮生长因子（EGF），产生比野生型具有更高EGFR结合亲和力的变异。这些结果表明，蛋白质功能可以忠实地以长度不可知的形式被捕获，从而实现自然蛋白质进化特征的那种协调的、大规模的序列修饰。
据介绍，蛋白质已经进化了数十亿年，通过协调的替换、插入和删除，但计算蛋白质设计不能完全复制大自然从现有模板中设计新蛋白质的能力。蛋白质语言模型生成信息丰富的每残基表示，但利用它们进行大规模的、保留功能的序列修改仍然遥不可及。
附：英文原文
Title: Miniaturizing and modifying natural proteins with Raygun
Author: Devkota, Kapil, Shonai, Daichi, Mao, Joey, Ko, Young Su, Wang, Wei, Soderling, Scott, Singh, Rohit
Issue&Volume: 2026-07-29
Abstract: Proteins have evolved over billions of years through coordinated substitutions, insertions and deletions, yet computational protein design cannot fully replicate nature’s ability to engineer new proteins from existing templates. Protein language models1,2,3 generate informative per-residue representations, but harnessing them for large-scale, function-preserving sequence modifications has remained beyond reach. Here we introduce Raygun, a generative artificial intelligence framework that enables miniaturization, modification and augmentation of proteins, using a probabilistic encoding of protein sequences constructed from language model embeddings. Our key conceptual advance is to encode each protein not as a sequence of variable length in high-dimensional space, but as a probability distribution in fixed dimensions, making proteins of any length directly commensurable. Controlled by just two parameters governing substitutions and length changes, Raygun can shrink proteins by 10–25% (sometimes more than 50%), expand them beyond their natural size, and introduce extensive sequence diversity, all while preserving predicted structural integrity and functional sites. In cell-based validation, Raygun miniaturized fluorescent proteins (2 shorter than 96% of fluorescent proteins in FPbase) and TurboID, a synthetic biotin ligase that has been widely adopted for proteomics. It also expanded epidermal growth factor (EGF), generating variants with higher EGFR-binding affinity than the wild type. These results show that protein function can be faithfully captured in a length-agnostic representation, enabling the kind of coordinated, large-scale sequence modifications that characterize natural protein evolution.
DOI: 10.1038/s41586-026-10842-8
Source: https://www.nature.com/articles/s41586-026-10842-8
主题：蛋白质|修饰|用Raygun实现天然蛋白质