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Structure, Dynamics and Energetics of Protein Unfolded States

蛋白质展开状态的结构、动力学和能量学

基本信息

批准号：
1330259
负责人：
Daniel Raleigh
金额：
$ 72万
依托单位：
SUNY at Stony Brook
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1330259&HistoricalAwards=false
关键词：
Structure Dynamics Energetics Protein Unfolded

项目摘要

The native state of a protein is the structure that is most thermodynamically stable and is normally the biologically active form. Protein folding begins from a less structured collection of states, commonly known as the denatured state ensemble (DSE). The DSE is considerably harder to study than the native state owing to its dynamic and flexible nature, and to the fact that the vast majority of protein molecules populate the native state under normal conditions. Nevertheless, understanding the DSE is fundamentally important for understanding of protein folding and stability. The stability of a protein is dictated by the free energy difference between the native state and the DSE, thus any changes in solution conditions or mutations that alter the DSE can alter stability and folding. The DSE is the reference state for stability measurements; much of our quantitative understanding of the specific interactions involved in stabilizing the native state of proteins is derived from experiments that make implicit assumptions about the DSE. In addition, the DSE can be the starting state for nonproductive protein aggregation, a process that impacts biotechnology and biology. This project is directed at fundamental studies of protein folding, focusing on the role of the DSE. A deeper understanding of the properties of the DSE and the role that the DSE plays in folding is required for a complete description of protein folding and aggregation. The DSE can be populated under harsh, non-physiological conditions, but progress requires characterization of the DSE under conditions that are relevant for folding and aggregation, i.e., under conditions where the native state is stable. Comparative experimental studies of a set of three representative model proteins will be carried out under physiologically relevant designed conditions. The experimental work will be closely integrated with efforts by theoretical collaborators. A range of educational and outreach activities are planned. An 'adopt a lab' program has been initiated as part of the first year undergraduate honors lab class and will be further developed. Interactions with Stony Brook University?s project WISE (Women in Science and Engineering) program will be established to provide support and encouragement to undergraduate women who are interested in science and engineering. Laboratory exercises will also be designed to interface with project WISE. Graduate and undergraduate training and mentoring are key components of the project. Outreach activities include visits and seminars at undergraduate institutions, as well as collaborations with researchers at primarily undergraduate institutions. The research goals of the project aim to answer fundamental questions in protein folding. As part of the work, new tools and methodologies will also be developed which can be applied to a range of problems in protein structure and dynamics beyond the area of protein folding.

蛋白质的天然状态是最稳定的结构，通常是生物活性形式。蛋白质折叠从结构较差的状态集合开始，通常称为变性状态集合（DSE）。由于DSE的动态性和灵活性，以及绝大多数蛋白质分子在正常条件下处于天然状态这一事实，DSE比天然状态更难研究。然而，理解DSE对于理解蛋白质折叠和稳定性至关重要。蛋白质的稳定性是由天然状态和DSE之间的自由能差决定的，因此溶液条件的任何变化或改变DSE的突变都会改变蛋白质的稳定性和折叠性。DSE是稳定性测量的参考状态；我们对稳定蛋白质天然状态所涉及的特定相互作用的定量理解，大部分来自于对DSE做出隐含假设的实验。此外，DSE可以成为非生产性蛋白质聚集的起始状态，这是一个影响生物技术和生物学的过程。该项目针对蛋白质折叠的基础研究，重点关注DSE的作用。为了完整地描述蛋白质的折叠和聚集，需要更深入地了解DSE的性质以及DSE在折叠中所起的作用。DSE可以在苛刻的非生理条件下填充，但进展需要在与折叠和聚集相关的条件下对DSE进行表征，即在原生状态稳定的条件下。一组具有代表性的三种模型蛋白的比较实验研究将在生理学相关的设计条件下进行。实验工作将与理论合作者的努力紧密结合。计划开展一系列教育和外联活动。一项“采用实验室”计划已经启动，作为第一年本科荣誉实验课的一部分，并将进一步发展。与石溪大学的互动？为支持和鼓励对理工科感兴趣的本科女生，将设立WISE （Women in Science and Engineering）项目。实验室练习也将被设计成与WISE项目相结合。研究生和本科生的培训和指导是该项目的关键组成部分。外联活动包括在本科院校访问和研讨会，以及与主要本科院校的研究人员合作。该项目的研究目标旨在回答蛋白质折叠的基本问题。作为工作的一部分，新的工具和方法也将被开发出来，这些工具和方法可以应用于蛋白质折叠领域以外的蛋白质结构和动力学的一系列问题。