Theoretical and Computational Studies of Pressure Induced Denaturation of Proteins

压力诱导蛋白质变性的理论和计算研究

• 批准号: 0543769
• 负责人: Angel Garcia
• 金额: $ 94.69万
• 依托单位: Rensselaer Polytechnic Institute
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0543769&HistoricalAwards=false
• 关键词: Theoretical; Computational; Studies; Pressure; Induced

The main objective of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Biological Physics Program in the Division of Physics in the Mathematical and Physical Sciences Directorate, is to establish relationship between the thermodynamics and the structural properties of pressure induced changes in proteins using molecular simulations. Pressure provides a way of shifting equilibrium of protein configurations without increasing thermal fluctuations or changing the system composition. Hydrostatic pressure provides a way of probing the role of hydration in protein stability and dynamics. In spite of the wealth of experimental information available, theoretical and computational studies of pressure denaturation have been limited by system size and the slow relaxation of proteins at high pressures. With the development of enhanced sampling techniques, the use of large distributed computing resources, and the development of coarse-grained models for protein folding, these limitations can be overcome. This project will study the effect of high pressure on the stability of peptides that are known to form alpha and beta hairpin structures to determine the effect that high pressure has on the secondary structure stability. To study the effect of tertiary interactions in protein stability, the PI will study the effect of pressure on the stability of mini proteins (Trp-cage) and a small protein (protein A), two systems with simple folds that involve the packing of secondary structure elements. A major challenge will be to study the effect of pressure on larger proteins, such as ubiquitin and SNase. The studies on large proteins will involve coarse-grained models, combined with umbrella sampling techniques on fully solvated systems. The models will be validated by comparing their results with those obtained in unbiased detailed calculations on smaller systems, and by making predictions that can be tested experimentally. The structure and thermodynamics of the unfolded and transition state ensembles to correlate volume effects measured thermodynamically to the degree of hydration of the various ensembles will be studied in detail. This work will establish a framework for understanding the role of water in protein function and stability, as well as for the interpretation of a number of experimental studies of pressure effects on biological molecules.This project is inherently interdisciplinary and it will be done in collaboration with theoretical, computational and experimental groups. Software, models, and algorithms developed in this project will be made available to the scientific community. Students at all levels will be trained in the modeling of thermodynamics properties of biomolecular systems. The PI will train graduate and undergraduate students from both Physics and Biology departments. To enhance the participation of under represented minorities in science, the PI will host researchers and students from the University of Puerto Rico Mayaguez and Humacao.

该项目的主要目的是由分子生物物理学在生物学科学局和细胞生物科学局中共同支持的，在数学和物理科学局的物理学部中，生物学和生物物理学计划是在数学和物理科学局中的，是为了在热力学和使用压力诱导的蛋白质变化的蛋白质变化之间建立蛋白质的关系之间的关系。压力提供了一种在不增加热波动或更改系统组成的情况下转移蛋白质构型平衡的方法。静液压提供了一种探测水合在蛋白质稳定性和动力学中的作用的方法。尽管有大量的实验信息可用，但压力变性的理论和计算研究受到系统大小和高压下蛋白质缓慢松弛的限制。随着增强的采样技术的开发，使用大型分布式计算资源以及用于蛋白质折叠的粗粒模型的开发，可以克服这些局限性。 该项目将研究高压对形成α和β发夹结构的肽稳定性的影响，以确定高压对二级结构稳定性的影响。为了研究三级相互作用在蛋白质稳定性中的影响，PI将研究压力对迷你蛋白质稳定性（TRP-cage）和小蛋白质（蛋白A）的稳定性的影响，这是两个具有简单折叠的系统，涉及二级结构元素的包装。一个主要的挑战将是研究压力对较大蛋白质的影响，例如泛素和SNase。关于大蛋白的研究将涉及粗粒模型，并结合完全溶剂化系统上的伞采样技术。这些模型将通过将其结果与在较小系统上无偏详细计算中获得的结果进行比较，并通过做出可以通过实验测试的预测来验证。 在热力学上测量的体积效应与各种合奏的水合程度相关联的结构和过渡状态集合的结构和热力学将进行详细研究。这项工作将建立一个框架，以了解水在蛋白质功能和稳定性中的作用，以及解释对生物分子的压力影响的许多实验研究。该项目本质上是跨学科的，它将与理论，计算，实验组合作进行。 该项目中开发的软件，模型和算法将提供给科学界。 各级学生将接受生物分子系统热力学特性的建模培训。 PI将培训来自物理和生物学系的毕业生和本科生。为了增强代表少数群体参与科学的参与，PI将接待波多黎各玛雅格大学和Humacao大学的研究人员和学生。