Computational Studies of Folding and Dynamics of Proteins

蛋白质折叠和动力学的计算研究

• 批准号: 1050966
• 负责人: Catherine Royer
• 金额: $ 86.12万
• 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: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1050966&HistoricalAwards=false
• 关键词: Computational; Studies; Folding; Dynamics; Proteins; Computational; Studies; Folding; Dynamics; Proteins

The mechanism of folding of proteins to their native structure is a subject of significant interest in biology. Proteins perform most of the molecular level functions in the cell. In addition, proteins are nanoscale molecular machines that can perform tasks important for biotechnology applications. It is well known that the marginal stability of proteins can be altered by changing solvent conditions, such as application of pressure, or addition of co-solvents. Computer simulations can provide an atomic level picture of the mechanisms by which solvent (mostly water), co-solvents, and physical effects, such as pressure and temperature, affect protein stability. The combined use of enhanced sampling methods and parallel computing enable the study of protein folding/unfolding equilibrium and dynamics. The objective of this project is to study the folding/unfolding equilibrium and kinetics of model proteins with increased degree of complexity. The simulations will explore the effects of co-solvents and hydrostatic pressure on the transition states and will help understand the effect of solvent in determining the transition state of proteins and will provide a measure of the folding/unfolding activation volumes. These calculations will be done on model proteins that fold in the microsecond timescale and for which there is ample kinetics and thermodynamics experimental data available. In addition to folding, this project will explore the functional dynamics of the proteins - that is, correlate the existence of sub-states in the energy landscape with functional states of the proteins. The overall goal is to examine the equilibrium folding/unfolding, the energy landscape, the folding kinetics and dynamics of protein domains involved in protein-protein interactions and switching. These proteins fold in the microsecond to 100 microsecond timescales. The kinetics and functional dynamics of these proteins will be studied using Markov state models built from a very large number of independent simulations. Theories related to the allosteric effect in proteins will be tested. This research is interdisciplinary in nature and includes the use of physical and computational methods to describe basic steps in the functioning of biological models. An important element of this project is the training of scientists with expertise in physics, biology and computational methods. This training will be done with students at various levels of education - including high school, undergraduate and graduate students, and postdoctoral fellows. Another equally important element of this research is the commitment to enhance participation of underrepresented groups in research. The PI's laboratory has continuously hosted and will continue to host minority and women undergraduates doing research in the group. Many of these students have now obtained PhDs or are pursuing graduate studies. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Physics of Living Systems Program in the Division of Physics in the Mathematical and Physical Sciences Directorate.

将蛋白质折叠为天然结构的机制是对生物学产生重大兴趣的主题。蛋白质在细胞中执行大部分分子水平功能。此外，蛋白质是纳米级分子机器，可以执行对生物技术应用重要的任务。 众所周知，蛋白质的边际稳定性可以通过改变溶剂条件（例如施加压力或添加共溶剂）来改变。计算机模拟可以提供原子水平的图像，描述了溶剂（主要是水），共溶剂和物理效应（例如压力和温度）会影响蛋白质稳定性。增强采样方法和平行计算的联合使用可以研究蛋白质折叠/展开平衡和动力学。该项目的目的是研究模型蛋白质的折叠/展开平衡和动力学，并具有增加的复杂程度。这些模拟将探索共溶剂和静水压力对过渡态的影响，并将有助于了解溶剂在确定蛋白质过渡状态中的影响，并将提供折叠/展开激活量的度量。这些计算将对在微秒时间尺度折叠的模型蛋白上进行，并为其提供充足的动力学和热力学实验数据。除折叠外，该项目还将探索蛋白质的功能动力学 - 也就是说，将能量景观中的子群的存在与蛋白质的功能态相关联。 总体目标是检查蛋白质 - 蛋白质相互作用和开关涉及的蛋白质结构域的均能折叠/展开，能量景观，折叠动力学和动力学。这些蛋白质在微秒中折叠至100微秒的时间尺度。这些蛋白质的动力学和功能动力学将使用Markov状态模型研究，该模型由大量独立模拟构建。将测试与蛋白质变构作用有关的理论。这项研究本质上是跨学科的，包括使用物理和计算方法来描述生物模型功能的基本步骤。该项目的一个重要组成部分是对具有物理，生物学和计算方法专业知识的科学家进行培训。 这项培训将与各种教育水平的学生进行，包括高中，本科生和研究生以及博士后研究员。这项研究的另一个同样重要的要素是致力于增强代表性不足群体的研究的承诺。 PI的实验室一直持续托管，并将继续接待少数民族和妇女的本科生在该小组中进行研究。这些学生中的许多学生现在已经获得了博士学位或正在攻读研究生学习。 该项目由分子生物物理学在生物科学局和生物科学局的分子和细胞生物科学划分中共同支持，而在数学和物理科学局的物理学部门的生命系统计划。