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Updated: May 23, 2025

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CasGen:CRISPR Cas蛋白设计的规范化生成模型,具有分类和基于边际的优化

Bharani Nammi¹, Vindi M Jayasinghe-Arachchige², Sita Sirisha Madugula²

¹Department of Industrial, Manufacturing and Systems Engineering, University of Texas at Arlington, Arlington, Texas, United States.

bioRxiv : the preprint server for biology

|March 10, 2025

概括

CasGen,一个新的AI模型,设计了用于基因组编辑的新型聚类正规间隔短Palindromic重复 (CRISPR) 相关 (Cas) 蛋白质. 这扩大了合成生物学和治疗应用的工具包,具有精确和多功能Cas变体.

科学领域:

生物技术是生物技术.
基因组学就是基因组学.
蛋白质工程是指蛋白质工程.

背景情况:

目前的基因组编辑依赖于一组有限的聚类定期间隔的短Palindromic重复 (CRISPR) 相关 (Cas) 蛋白质,主要是Cas9和Cas12变体.
这种限制限制了基因组工程应用的范围和多功能性.

研究的目的:

开发一种新的深度生成模型,CasGen,用于设计新的Cas9和Cas12蛋白质.
为了提高产生的Cas蛋白质的质量和功能完整性,用于更广泛的基因组编辑应用.

主要方法:

利用基于变压器的深度生成模型 (CasGen) 与基于边际的潜空间规范化.
针对非Cas序列过的综合分类,用于指导设计的贝叶斯优化,以及基于AlphaFold的结构验证.
编制了来自InterPro和PDB的3,021个Cas9,597个Cas12和597个非Cas蛋白序列的数据集.

主要成果:

通过AlphaFold2/3.3.2,生成的Cas9和Cas12蛋白与已知的变体具有很高的结构相似性 (TM分数为0.70-0.85,RMSD<2.00 Å).
序列身份分析揭示了新的Cas9基因 (28-55%的同一性) 和Cas12a变体 (多达48%的同一性).
BLAST 分析证实了生成的序列的新性,过了非常相似的现有 Cas 蛋白.

结论:

CasGen模型成功设计了多样化和功能健全的Cas蛋白质,显著扩大了基因组编辑工具包.
这种深层次的生成方法对推进合成生物学和开发更精确,更通用的基于Cas的治疗工具具有前景.

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