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Accelerating conformational transitions in binding flexible proteins

加速结合柔性蛋白的构象转变

基本信息

批准号：
1817332
负责人：
Jianhan Chen
金额：
$ 60万
依托单位：
University of Massachusetts Amherst
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1817332&HistoricalAwards=false
关键词：
Accelerating conformational transitions binding flexible

项目摘要

Proteins are biological macromolecules that control virtually all aspects of cellular functions, ranging from enzyme catalysis, response to external stimuli, to control of cell cycle and cell fate decision. For function, proteins have evolved to possess unique three-dimensional (3D) structural properties. This project focuses on an important newly recognized class of proteins that exploit highly flexible 3D structures for function. These proteins include so-called intrinsically disordered proteins (IDPs) that account for about one-third of all eukaryotic proteins and are key components of cellular signaling and regulatory networks. This project will develop efficient computational methods for simulating flexible proteins and uncover the fundamental principles of how structural disorder mediates protein function. The new computational tools will be made available to the broad scientific community and can be applied to study biomolecular dynamics and interactions in general. Besides training of graduate and undergraduate students, the PI will contribute to various outreach programs in western Massachusetts that engage women and other under-represented minorities in STEM fields. He will also help expand an informal science education project known as the "Molecular Playground", which installs interactive molecular displays in public spaces such as schools, museums, shopping malls and airports. This project will add much-needed contents with protein dynamics, such as to illustrate the fascinating phenomenon how extreme conformational flexibility of IDPs support function. The overarching research objective of this project is to determine the fundamental principles that allow flexible proteins such as IDPs to undergo rapid binding-induced folding or unfolding for viable cellular signaling. Greater utilization of flexible proteins such as IDPs have been associated with increasingly sophisticated signaling in complex multicellular organisms. However, the frequent requirement of large-scale conformational transitions for binding flexible proteins can lead to a potential kinetic bottleneck detrimental to effective cellular signaling. It is hypothesized that long-range electrostatic interactions between enriched charges on IDPs and their binding targets play a key role in promoting facile binding. A specific hypothesis to be tested is that long-range electrostatic forces not only accelerate IDP encounter, but also promote folding-competent encounter topologies to allow efficient folding upon encounter. This project will also tackle an emerging phenomenon known as regulated unfolding in cellular signaling and determine how transient hydrophobic interactions may reduce transition barriers and contribute to efficient coupled binding, folding and unfolding in Bcl-2 family proteins. To test these hypotheses, new GPU-accelerated, implicit solvent-based atomistic simulation techniques will be developed to enable efficient calculation of the free energy, pathway and kinetics of binding-induced large-scale protein conformational transitions. Results from equilibrium and kinetic simulations will be validated using existing mechanistic and kinetic data as well as new measurements performed in collaboration with experimental labs. This project is supported by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences with partial co-funding from the Chemical Theory, Models and Computational methods (CTMC) Program in the Division of Chemistry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

蛋白质是生物大分子，几乎控制细胞功能的所有方面，从酶催化，对外部刺激的反应，到控制细胞周期和细胞命运决定。对于功能，蛋白质已经进化到具有独特的三维（3D）结构特性。该项目的重点是一类重要的新认识的蛋白质，利用高度灵活的3D结构的功能。这些蛋白质包括所谓的内在无序蛋白（IDP），占所有真核蛋白质的三分之一，是细胞信号传导和调控网络的关键组成部分。该项目将开发用于模拟柔性蛋白质的有效计算方法，并揭示结构紊乱如何介导蛋白质功能的基本原理。新的计算工具将提供给广大的科学界，并可应用于研究生物分子动力学和一般的相互作用。除了对研究生和本科生的培训外，PI还将为马萨诸塞州西部的各种外展项目做出贡献，这些项目将吸引妇女和其他代表性不足的少数民族参与STEM领域。他还将帮助扩大一个名为“分子游乐场”的非正式科学教育项目，该项目在学校、博物馆、购物中心和机场等公共场所安装互动分子显示器。该项目将增加急需的内容与蛋白质动力学，如说明如何极端构象灵活性的IDPs支持功能的迷人现象。该项目的首要研究目标是确定允许柔性蛋白质（如IDP）进行快速结合诱导折叠或展开以实现可行细胞信号传导的基本原理。柔性蛋白质如IDP的更大利用与复杂多细胞生物中日益复杂的信号传导相关。然而，结合柔性蛋白质的大规模构象转变的频繁需求可能导致对有效细胞信号传导有害的潜在动力学瓶颈。据推测，在IDP和它们的结合目标上的富集电荷之间的长程静电相互作用在促进容易的结合中起关键作用。一个具体的假设进行测试的是，远程静电力不仅加速IDP遇到，但也促进折叠主管遇到拓扑结构，以允许有效的折叠后遇到。该项目还将解决一种称为细胞信号传导中的调节展开的新兴现象，并确定瞬时疏水相互作用如何减少过渡障碍，并有助于Bcl-2家族蛋白的有效耦合结合，折叠和展开。为了验证这些假设，将开发新的GPU加速的隐式溶剂型原子模拟技术，以有效计算结合诱导的大规模蛋白质构象转变的自由能、途径和动力学。平衡和动力学模拟的结果将使用现有的力学和动力学数据以及与实验室合作进行的新测量进行验证。该项目由分子和细胞生物科学部的分子生物物理学小组支持，部分资金来自化学部的化学理论，模型和计算方法（CTMC）计划。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。