近日，北京大学伊成器团队的论文发现了使用基于AlphaFold3的接触建模进行精确的DNA碱基编辑建模。这一研究成果发表在2026年7月22日出版的国际学术期刊《自然》上。

在这里，该课题组提出了ContactSeek，这是一个人工智能驱动的框架，主题是AlphaFold3 （AF3）预测接触概率，以提高基因组编辑器的特异性。使用Cas9-TadA腺嘌呤碱基编辑器作为示范，课题组绘制了它们的全基因组脱靶DNA序列，并将脱靶DNA序列输入AF3。在AF3输出中，该课题组发现接触概率比预测的三维结构更敏感，用于检测靶标和脱靶复合物之间的差异相互作用。ContactSeek将接触概率与基于测序的脱靶信号相关联，识别并排序了共识接触区域，这些区域是与DNA/引导RNA具有一致接触变化的邻近Cas残基，并在其中精确定位了特异性决定残基。

ContactSeek也可以模块化应用并识别TadA8e脱氨酶中的关键残基。靶向扩增子测序、全基因组分析、R-loop分析和RNA测序共同证实了特异性大大增强；他们的最佳变体，结合了Cas9和TadA8e的两个突变，优于几种已知的高保真腺嘌呤碱基编辑器。ContactSeek也被推广到基于Cas12的胞嘧啶碱基编辑器。总的来说，他们的框架代表了一个为特异性改进量身定制的af3驱动模型，通过整合结构和功能维度，为提高基因组编辑工具的精度建立了一个范例。

据介绍，实现生化转化的高特异性对研究和治疗至关重要。这对于基因组编辑尤其重要，因为增强工具特异性可确保有效和精确的编辑结果。目前的策略受到活动特异性权衡、高劳动强度和低成功率的限制。

附：英文原文

Title: Precise DNA base editing using AlphaFold3-based contact modelling

Author: Meng, Haowei, Lei, Zhixin, Yan, Yongchang, Wang, Liren, Zhang, Sihan, Rao, Xichen, Shao, Chuyun, Zhang, Xiaoting, Chen, Ke, Yang, Lei, Liu, Rongrong, Yang, Gaohui, Shen, Ruoyu, Gu, Ruichu, Wang, Xinyan, Wang, Yiya, Lu, Suiru, Lv, Zhicong, He, Bo, Wen, Han, Li, Dali, Yi, Chengqi

Issue&Volume: 2026-07-22

Abstract: Achieving high specificity in biochemical transformations is crucial for research and therapeutics. This is particularly important for genome editing, where enhancing tool specificity ensures effective and precise editing outcomes1,2. Current strategies are constrained by activity-specificity trade-offs, high labour intensity and low success rates3,4. Here we present ContactSeek, an artificial-intelligence-driven framework that uses AlphaFold3 (AF3)-predicted contact probability5 to improve the specificity of genome editors. Using Cas9–TadA adenine base editors6,7,8 as a demonstration, we mapped their genome-wide off-targets and fed the off-target DNA sequences to AF3. Among AF3 outputs, we found that contact probability was more sensitive than predicted three-dimensional structures for detecting differential interactions between on- and off-target complexes. Correlating contact probability with sequencing-based off-target signals, ContactSeek identified and ranked consensus contact regions, which are neighbouring Cas residues with consistent contact changes to DNA/guide RNA, and pinpointed specificity-determining residues within them. ContactSeek can also be applied modularly and identified key residues in the TadA8e deaminase. Targeted amplicon sequencing, genome-wide profiling, R-loop assay and RNA-sequencing together confirmed the greatly enhanced specificity; our best variant, combining two mutations of Cas9 and TadA8e, outperformed several known high-fidelity adenine base editors. ContactSeek is also generalized to Cas12a-based cytosine base editors. Collectively, our framework represents an AF3-driven model tailored for specificity improvement, establishing a paradigm for improving the precision of genome editing tools through the integration of structural and functional dimensions.

DOI: 10.1038/s41586-026-10794-z

Source: https://www.nature.com/articles/s41586-026-10794-z