蛋白 CREATE 能够实现 de novo 合成蛋白质结合剂的闭环设计
Alec Lourenço1, Arjuna Subramanian1, Ryan Spencer2
1Caltech.
bioRxiv : the preprint server for biology
|January 13, 2025
概括
蛋白质设计由蛋白质创建 (Protein CREATE) 推进,这是一个整合计算和实验的新管道. 该系统快速生成和测试新型蛋白质结合剂,改进未来蛋白质工程的大型语言模型.
科学领域:
- 蛋白质工程和设计
- 计算生物学 计算生物学
- 生物技术是生物技术.
背景情况:
- 蛋白质在治疗和催化中很有价值,但很难设计,通常依赖于屏幕或定向进化.
- 蛋白质大语言模型 (LLM) 可以生成多种序列,但缺乏实验验证和模型更新方法.
- 在规模上对计算设计的蛋白质进行表征是蛋白质工程中的一个重大瓶.
研究的目的:
- 介绍蛋白质创建,一个集成的计算和实验管道,用于大规模的蛋白质表征.
- 以实验性结合数据来更新蛋白质LLM,以提高设计准确性.
- 为了发现新的蛋白质结合剂,并了解连接体-受体结合特征.
主要方法:
- 开发了蛋白质CREATE,将计算设计与实验分析结合起来,使用下一代测序和菌体显示.
- 采用单分子读数来进行定量约束数据收集.
- 利用并行阳性和阴性选择来识别IL-7受体α和胰岛素受体的目标结合物.
主要成果:
- 生成并测试了数千种设计的蛋白质结合剂,确定了IL-7受体α和胰岛素受体的新型候选者.
- 发现了关键的联体受体结合特征,包括IL7Rα的保留水接口和胰岛素受体的多种结合模式.
- 验证了结构特征的重要性 (例如,缺少未配对的氨酸) 并评估了像iPTM这样的计算指标的预测能力.
结论:
- 蛋白质创建提供了一个可扩展的框架,用于实验验证和改进计算设计的蛋白质.
- 收集的数据成功更新了生成模型,证明了闭环设计-制造-测试周期的潜力.
- 这种方法促进了蛋白质结合剂的细粒度设计,并推动了蛋白质工程领域的进步.
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