生物质谱环境下固定无序蛋白复合物结构预测方法的开发和应用

固定无序蛋白（IDP）复合物在人类健康和细胞功能调控中起着至关重要的作用，它们是一类在体内广泛分布且与重大疾病相关的新颖靶标。为开展基于结构的合理药物设计，确定IDP复合物的三维结构和构象行为变得尤为重要与紧迫。近年来，质谱逐渐发展为研究IDP复合物构象信息及其结构蛋白质组学不可或缺的工具之一。然而，目前人们对IDP复合物在质谱环境下的高分辨结构信息还一无所知。因此，我们拟在本项目中开发一套基于分子模拟技术的方法，对两种典型且与重大疾病相关的IDP复合物在质谱环境下的三维结构进行精准预测，并应用已知质谱实验数据对计算模拟结果进行验证。在此基础上，我们将系统地研究IDP复合物在生物质谱环境下的结构和动力学行为，及其气相物理化学性质在谱图上的反映。本项目所开发的技术方法和路线将极大的丰富人们对IDP复合物以及质谱分析的认知，并推动我国在IDP复合物靶标药物设计及其分析学研究的创新性发展。

Intrinsically disordered protein (IDP) complexes play a pivotal role in human health and cellular functional regulations. They are widespread and important for the design of novel drugs. Developing potential drugs targeting IDP complexes requires structural characterization of these complexes. A very attractive tool of structural proteomics of IDP complexes is represented by mass spectrometry (MS), which conjugates the unique analytical power and high-throughput potential of MS with structural investigation in vacuum. However, MS alone cannot provide high-resolution structural information of IDP complex in the gas phase. Here, we plan to develop a molecular simulation-based protocol for the structural prediction of IDP complex under MS conditions. Specifically, we will apply such protocol to accurately predict the structural information of two typical and disease-related IDP complexes. Our calculations will be validated by reproducing available experimental MS data. Based on our work, we will systematically investigate the structural and dynamic behaviors of IDP complexes under MS conditions, as well as their reflections on spectrum. The protocol developed here will be useful to enlarge the molecular insight into IDP complex and MS analysis. It will also impact the development of IDP complex-based drug design and relevant analytical tools.