精确模拟蛋白质二次结构和液体-液体相分离之间的合
Yumeng Zhang1, Shanlong Li1, Xiping Gong1
1Department of Chemistry, University of Massachusetts, Amherst, MA 01003, USA.
bioRxiv : the preprint server for biology
|September 4, 2023
概括
一个新的混合分辨率 (HyRes) 蛋白质模型准确地捕捉了液-液相分离 (LLPS) 期间内在无序蛋白质 (IDP) 中的骨干相互作用和次要结构. 这一进步使LLPS的精确模拟成为可能,揭示了推动该过程的关键因素.
科学领域:
- 计算生物学 计算生物学
- 生物物理学的生物物理.
- 蛋白质动力学 蛋白质动力学
背景情况:
- 内在无序的蛋白质 (IDPs) 驱动液体-液体相分离 (LLPS),这对于无膜有机体的形成至关重要.
- 目前的粗粒度 (CG) 模型,就像Cα-only一样,在LLPS期间表示IDP骨干相互作用和次要结构时缺乏准确性.
- 需要精确的建模来理解控制IDP相位分离的特定序列机制.
研究的目的:
- 引入和验证一个混合分辨率 (HyRes) 蛋白模型来模拟IDP LLPS.
- 评估HyRes准确预测二级结构倾向,链条尺寸和LLPS行为的能力.
- 研究LLPS在IDP中的分子决定因素,包括瞬态二次结构的作用.
主要方法:
- 开发了一种混合分辨率 (HyRes) 模型,具有原子化骨干和粗粒度侧链.
- 使用HyRes.23模拟了IDP GY-23的自发相位分离.
- 分析了单一突变和与疾病相关的突变对LLPS倾向性和二次结构形成的影响.
- 研究了TDP-43保存区域 (CR) 和其突变的相分离.
主要成果:
- HyRes准确地预测了单体IDP螺旋倾向和链条尺寸.
- 对GY-23的模拟表明了自发的LLPS和对单个突变的敏感性.
- HyRes成功地预测了凝结物中β-片形成的增加以及对TDP-43 CR螺旋性和LLPS的复合突变效应.
- LLPS的倾向是由骨干和侧链相互作用的平衡决定的,而不是单独的螺旋性.
结论:
- 该HyRes模型为IDP相分离的分子模拟提供了显著的进步.
- LLPS倾向是由骨干和侧链相互作用的相互作用决定的,而不仅仅是螺旋性.
- HyRes将有助于更深入地了解国内流离失所者中过渡性次要结构和LLPS之间的合.
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