用AlphaFold预测PROTAC介导的蛋白质-蛋白质接口的挑战揭示了小接口的一般限制
Gilberto P Pereira1,2, Corentin Gouzien3, Paulo C T Souza1,2
1Laboratoire de Biologie et Modelisation de la Cellule, Ecole Normale Superieure de Lyon, CNRS, UMR 5239, Universite Claude Bernard Lyon 1, Inserm, U1293, Lyon F-69364, France.
Bioinformatics advances
|March 27, 2025
概括
AlphaFold2难以预测具有小接口的蛋白质复合体,阻碍了蛋白质分解向奇美拉 (PROTAC) 药物设计. 这种局限性即使在较新的版本中也存在,影响了针对向蛋白质降解疗法的计算建模.
科学领域:
- 结构生物学是结构生物学.
- 计算化学是一种计算化学.
- 药物发现 药物发现
背景情况:
- 蛋白质分解向化马体 (PROTACs) 是诱导向蛋白质降解的异构功能分子,为癌症提供了一个有前途的治疗策略.
- 准确预测PROTAC介导的蛋白质复合体对于*in silico*药物设计管道至关重要.
- 之前的观察表明AlphaFold2 (AF2) 在预测PROTAC介导复合体方面存在局限性.
研究的目的:
- 调查AlphaFold2在预测PROTAC介导蛋白质复合体方面的失败的根本原因.
- 评估接口大小和连接体存在对AF2预测准确性的影响.
- 为了将AlphaFold3 (AF3) 与AF2进行比较,用于PROTAC复杂预测.
主要方法:
- 分析了326种蛋白质异构体,以根据接口大小和连接体存在来评估AF2的性能.
- 对具有不同接口大小的复合体的AF2-多元预测的评估.
- 在28个PROTAC介导的二次数数据集上对AF2和AF3进行基准测试.
主要成果:
- AF2预测对接口大小敏感,对较小的接口观察到显著的不准确性,即使没有连接体.
- 对于PROTAC介导的二元预测,AF3的准确性没有比AF2显著提高.
- 在预测小接口方面,AF2的局限性对计算 PROTAC 设计和其他涉及小接口的预测任务具有关键意义.
结论:
- 在预测蛋白质复合体方面,AlphaFold2的准确性受到接口大小的显著影响,特别是对于小型接口.
- 观察到的局限性对化向金马的*in silico*设计构成了挑战,这些金马通常涉及小的交互接口.
- 需要进一步开发,以提高蛋白质结构预测工具的精度,用于具有小接口的复合体,这对于推进药物发现管道至关重要.
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