Disordered Proteins and Dynamic Interactions in Biology and Diseases.

项目摘要/摘要 最近认识到内在无序蛋白(IDPs)在生物学和人类疾病中的流行 挑战了蛋白质功能需要稳定结构的传统范式。此外，许多 已经发现，即使在特定的复合体和功能组件中，国内流离失所者仍然保持无序。这些 新的发现极大地扩展了蛋白质结构-功能中“结构”的含义 范式，包括从无序的系综到定义明确的构象的连续体。重要的是，这些 无序的蛋白质和动态的相互作用是调控网络的中心组成部分 细胞决策的几乎所有方面。它们与越来越多的人类疾病有关 包括癌症、神经退行性疾病、糖尿病和心脏病。因此，迫切需要 建立构象无序如何调节蛋白质功能的分子基础，以便了解如何 这些作用机制可能在疾病中受到干扰，也可能被药物分子拯救用于治疗。这个 实现这些首要目标的关键挑战是对无序蛋白质的定量描述 在相关的生物和疾病背景下的国家。平均结构性能的实验测量 单独的不足以定义无序的蛋白质集合，而可靠的分子模拟有一个 发挥关键和变革性的作用。该项目旨在继续发展先进的分子建模 和模拟方法，可以提供对无序蛋白质状态的准确描述，扩展了 可访问的时间和长度范围，并增强我们在分子水平上接受关键问题的能力 生物医学研究。通过战略选择的实验合作，该项目将进一步解决 围绕几个具有重大生物医学意义的系统提出的问题和问题：1)建立 序列-结构-功能-疾病的关系，我们将确定多位点磷酸化和 癌症相关突变调节反式激活结构域的结构、动态和相互作用 (TAD)肿瘤抑制基因P53；2)为了开发针对无序蛋白质状态的有效策略，我们 将通过动态研究确定抗癌药物EGCG如何抑制P53-TAD的分子基础 研究黄病毒蛋白水解酶的功能动力学和抑制作用；3)了解动态 在蛋白质-蛋白质相互作用的相关背景下，我们将确定分子基础是如何 伴侣Hsp70实现选择性混杂，帮助细胞应对蛋白质折叠挑战，以及如何 金黄色葡萄球菌新的毒力蛋白家族Spin抑制人髓过氧化物酶逃避 宿主先天免疫防御。集成的计算和实验方法部署在这些 研究将使我们能够将我们的计算方法开发努力引导到取得进展的关键领域 是必要的，同时用切实的反馈推动和测试我们的方法。 1

Project Summary/Abstract Recent recognition of the prevalence of intrinsically disordered proteins (IDPs) in biology and human diseases has challenged the traditional paradigm that stable structure is required for protein function. Furthermore, many IDPs have been found to remain disordered even in specific complexes and functional assemblies. These discoveries have now dramatically expanded the meaning of “structure” in the protein structure-function paradigm, to include a continuum from disordered ensembles to well-defined conformations. Importantly, these disordered proteins and dynamic interactions are central components of the regulatory networks that dictate virtually all aspects of cell decision-making. They are associated with a growing number of human diseases including cancers, neurodegenerative diseases, diabetes and heart diseases. There is thus a crucial need to establish the molecular basis of how conformational disorder mediates protein function, so as to understand how these functional mechanisms may be perturbed in diseases, or rescued by drug molecules for therapeutics. The key challenge towards achieving these overarching goals is quantitative description of the disordered protein states in relevant biological and disease contexts. Experimental measurements of averaged structural properties alone are inadequate to define the disordered protein ensemble, and reliable molecular simulations have a crucial and transformative role to play. This project aims to continue to develop advanced molecular modeling and simulation methodologies that can provide accurate description of disordered protein states, expand the accessible time and length scales, and enhance our ability to embrace critical questions in molecular level biomedical research. Through strategically chosen experimental collaborations, this project will further tackle questions and problems centered around several systems of great biomedical significance: 1) To establish the sequence-structure-function-disease relationship of IDPs, we will determine how multisite phosphorylation and cancer-associated mutations modulate the structure, dynamics and interactions of the transactivation domain (TAD) of tumor suppressor p53; 2) To develop effective strategies for targeting disordered protein states, we will determine the molecular basis of how the anti-cancer drug EGCG inhibits p53-TAD through dynamic interactions and study the functional dynamics and inhibition of flaviviral proteases; 3) To understand dynamic protein-protein interactions in relevant contexts, we will determine the molecular basis of how molecular chaperone Hsp70 achieves selective promiscuity to help the cell cope with protein folding challenge and how a novel family of virulence protein named SPIN from S. aureus inhibits human myeloperoxidase for evading the host innate immune defense. Integrated computational and experimental approaches deployed throughout these studies will enable us to direct our computational method development efforts to critical areas for which advances are needed, while at the same time push and test our methods with tangible feedback. 1