Theoretical and Computational Studies of Pressure Induced Denaturation of Proteins

该项目的主要目标是，由生物科学理事会分子和细胞生物科学部的分子生物物理学和数学和物理科学理事会物理学部的生物物理学计划共同支持，利用分子模拟建立热力学和压力诱导蛋白质变化的结构特性之间的关系。压力提供了一种在不增加热波动或改变系统组成的情况下改变蛋白质构型平衡的方法。流体静压提供了一种方法来探测蛋白质稳定性和动力学中水合作用。尽管有丰富的实验信息，压力变性的理论和计算研究受到系统大小和蛋白质在高压下缓慢松弛的限制。随着增强的采样技术的发展，大型分布式计算资源的使用，以及蛋白质折叠的粗粒度模型的发展，这些限制可以被克服。 该项目将研究高压对已知形成α和β发夹结构的肽的稳定性的影响，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对蛋白质稳定性的影响，PI将研究压力对微型蛋白质（Trp笼）和小蛋白质（蛋白质A）稳定性的影响，这两个系统具有简单的折叠，涉及二级结构元件的包装。一个主要的挑战将是研究压力对较大蛋白质的影响，如泛素和SNase。对大蛋白质的研究将涉及粗粒度模型，结合完全溶剂化系统的伞形采样技术。这些模型将通过将其结果与在较小系统上进行无偏详细计算所获得的结果进行比较，并通过做出可以通过实验进行检验的预测来进行验证。 展开和过渡态合奏的结构和热力学相关的体积效应测量的各种合奏的水化程度进行了详细研究。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，以及解释压力对生物分子影响的一些实验研究。该项目本质上是跨学科的，它将与理论，计算和实验小组合作完成。 该项目开发的软件、模型和算法将提供给科学界。 所有级别的学生都将接受生物分子系统热力学性质建模的培训。 PI将培训物理和生物系的研究生和本科生。为了加强代表性不足的少数群体对科学的参与，PI将接待来自波多黎各马亚圭斯大学和乌马考大学的研究人员和学生。

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.