Atomic functional site scaffolding in biopolymers with RFdiffusion3

IF 47.3 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2026-10-15 DOI:10.1126/science.aeh2982

Jasper Butcher, Rohith Krishna, Raktim Mitra, Seth M. Woodbury, Donghyo Kim, Rafael I. Brent, Yanjing Li, Nathaniel Corley, Andrew Favor, Anqi Chen, Paul T. Kim, Jonathan Funk, Gabriela Bastidas Reinoso, Kejia Wu, Aiko Muraishi, Helen E. Eisenach, Saman Salike, Simon Mathis, Tuscan Rock Thompson, Antonia Ruder, Enisha Sehgal, Andrew Kubaney, Jie Chen, Yuliya Politanska, Brian Coventry, Odin Zhang, Florence J. Hardy, Bo Qiang, Kieran Didi, Maxwell Kazman, Lars L. Schaaf, Frank DiMaio, David Baker

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Abstract

The catalytic and other sophisticated functions of biomolecules arise from the placement of many atoms in three-dimensional space. Here, we describe a generative artificial intelligence method for biopolymers, RFdiffusion3 (RFD3), which employs free atom diffusion to satisfy complex sets of atomic constraints more rapidly and accurately than previous methods across several challenges from enzyme design to RNA structure design. We demonstrate experimentally the power of the RFD3 pipeline for enzyme design by designing de novo phosphotriesterases with a complex active site architecture incorporating a carbamylated lysine coordinating two metal ions and zinc proteases specific for the transthyretin protein involved in amyloid diseases; in both cases we obtain active catalysts in zero shot 96 construct design campaigns.

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基于射频扩散的生物聚合物原子功能位点脚手架研究

生物分子的催化和其他复杂功能源于许多原子在三维空间中的放置。在这里，我们描述了一种生物聚合物的生成式人工智能方法，RFdiffusion3 (RFD3)，它利用自由原子扩散来满足复杂的原子约束集，比以前的方法更快、更准确地跨越了从酶设计到RNA结构设计的几个挑战。我们通过实验证明了RFD3管道在酶设计方面的能力，通过设计具有复杂活性位点结构的新磷酸三酯酶，该活性位点结构包括协调两种金属离子的氨甲酰赖氨酸和淀粉样蛋白疾病中涉及的转甲状腺素蛋白特异性锌蛋白酶；在这两种情况下，我们获得了活性催化剂零射击96结构设计活动。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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