通过动力蒙特卡洛模拟来合理化蛋白质-蛋白质相互作用在向蛋白质降解中的功能作用
Zhaoqian Su1, Shanye Yin2, Yinghao Wu3
1Data Science Institute, Vanderbilt University, 1001 19th Ave S, Nashville, TN, 37212.
bioRxiv : the preprint server for biology
|October 10, 2024
概括
向性蛋白质降解利用蛋白质溶解向化马体 (PROTACs) 等分子将疾病蛋白和结合酶结合在一起. 这项研究模拟了这些相互作用,发现积极的合作性有助于原生复杂的形成,这对药物开发至关重要.
科学领域:
- 生物化学 生物化学
- 计算生物学 计算生物学
- 药物发现 药物发现 药物发现
背景情况:
- 向蛋白质降解是一种新的治疗方法,用于因缺乏传统药物结合部位的蛋白质引起的疾病.
- 化向基因组 (PROTACs) 通过在蛋白和基酶之间形成三元复合物来促进向性降解.
- 了解蛋白质-蛋白质相互作用和结合合作性对于建模这一过程至关重要,这是计算工具仍在发展的领域.
研究的目的:
- 开发用于建模向蛋白质降解的计算工具,重点关注蛋白质-蛋白质相互作用的影响.
- 研究结合性合作性在PROTAC介导的降解过程中三元复合物的形成中的作用.
- 为了建立一个三元复杂结构的基准来模拟蛋白质协会.
主要方法:
- 构建更新的三元复合体的非冗余结构基准.
- 应用动态蒙特卡洛方法来模拟连接酶和PROTAC向蛋白质之间的关联.
- 通过不同的接口分析蛋白质-蛋白质关联,包括分子对接的接口.
主要成果:
- 具有正合作性的复合体中的蛋白质更有可能形成与原生类型的配置.
- 具有负合作性的复合体中的蛋白质在形成本地类配置时表现出更高的失败率.
- 与原生类型的绑定接口比替代接口具有更高的关联概率,特别是在积极合作的复合体中.
结论:
- 针对性蛋白质降解中的三元复合体形成受到底层二元蛋白质-蛋白质相互作用的显著调节.
- 开发的计算方法提供了关于蛋白质-蛋白质相互作用在PROTAC诱导的三元复合体形成中的作用的见解.
- 这项工作可以帮助设计更有选择性的PROTAC,用于向蛋白质降解疗法.
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