Disordered Proteins and Dynamic Interactions in Biology and Diseases.

生物学和疾病中的无序蛋白质和动态相互作用。

• 批准号: 10330292
• 负责人: Jianhan Chen
• 金额: $ 37.98万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330292
• 关键词: Address; Antineoplastic Agents; Area; Biological; Biology; Biomedical Research; Cells; Collaborations; Complex; Computing Methodologies; Decision Making; Diabetes Mellitus; Disease; Epigallocatechin Gallate; Family; Feedback; Goals; Heart Diseases; Human; Immune; Length; Malignant Neoplasms; Measurement; Mediating; Methodology; Methods; Molecular; Molecular Chaperones; Molecular Conformation; Mutation; Names; Natural Immunity; Neurodegenerative Disorders; Peptide Hydrolases; Peroxidases; Pharmaceutical Preparations; Phosphorylation; Play; Prevalence; Process; Property; Proteins; Research; Role; Signal Transduction; Staphylococcus aureus; Structure; System; TP53 gene; Testing; Therapeutic; Time; Transactivation; Virulence; human disease; insight; method development; models and simulation; molecular modeling; novel; protein aggregation; protein folding; protein function; protein misfolding; protein protein interaction; protein structure function; simulation; virtual

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

项目概要/摘要 最近认识到本质无序蛋白 (IDP) 在生物学和人类疾病中的普遍存在 挑战了蛋白质功能需要稳定结构的传统范式。 研究发现，即使在特定的复合物和功能组件中，IDP 仍保持无序状态。 现在的发现极大地扩展了蛋白质结构-功能中“结构”的含义 范式，包括从无序集合到明确定义的构象的连续体。 无序蛋白质和动态相互作用是决定的调控网络的核心组成部分 事实上，细胞决策的所有方面都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。 建立构象紊乱如何介导蛋白质功能的分子基础，从而了解如何 这些功能机制可能在疾病中受到干扰，或者被用于治疗的药物分子拯救。 实现这些总体目标的关键挑战是对无序蛋白质的定量描述 平均结构特性的实验测量。 单独的方法不足以定义无序的蛋白质整体，可靠的分子模拟具有 该项目旨在继续开发先进的分子模型。 和模拟方法，可以提供无序蛋白质状态的准确描述，扩展 可访问的时间和长度尺度，并增强我们在分子水平上接受关键问题的能力 通过战略性选择的实验合作，该项目将进一步解决生物医学研究问题。 围绕几个具有重大生物医学意义的系统的疑问和问题：1）建立 IDP 的序列-结构-功能-疾病关系，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、动力学和相互作用 (TAD) 肿瘤抑制因子 p53；2) 为了开发针对无序蛋白质状态的有效策略，我们 将确定抗癌药物EGCG如何通过动态抑制p53-TAD的分子基础 相互作用并研究黄病毒蛋白酶的功能动态和抑制 3) 了解动态； 在相关背景下蛋白质-蛋白质相互作用，我们将确定分子如何相互作用的分子基础 分子伴侣 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 来自金黄色葡萄球菌的名为 SPIN 的新型毒力蛋白家族抑制人髓过氧化物酶以逃避 宿主先天免疫防御在这些过程中部署了综合计算和实验方法。 研究将使我们能够将我们的计算方法开发工作引导到取得进展的关键领域 需要，同时通过切实的反馈来推动和测试我们的方法。 1