Computational Studies of Folding and Dynamics of Proteins

蛋白质折叠成天然结构的机制是生物学中非常感兴趣的课题。蛋白质在细胞中执行大多数分子水平的功能。此外，蛋白质是纳米级的分子机器，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来改变，例如施加压力或添加共溶剂。计算机模拟可以提供一幅原子水平的图像，了解溶剂(主要是水)、共溶剂以及压力和温度等物理效应影响蛋白质稳定性的机制。结合使用增强的采样方法和并行计算，可以研究蛋白质折叠/去折叠的平衡和动力学。这个项目的目的是研究复杂程度增加的模型蛋白质的折叠/去折叠的平衡和动力学。这些模拟将探索共溶剂和静水压力对过渡态的影响，将有助于理解溶剂在确定蛋白质过渡态时的影响，并将提供折叠/展开激活体积的测量。这些计算将在微秒时间尺度内折叠的模型蛋白质上进行，并且有大量的动力学和热力学实验数据可用。除了折叠，这个项目还将探索蛋白质的功能动力学--也就是说，将能量格局中亚状态的存在与蛋白质的功能状态联系起来。总体目标是研究蛋白质-蛋白质相互作用和转换中涉及的蛋白质结构域的平衡折叠/展开、能量格局、折叠动力学和动力学。这些蛋白质在微秒到100微秒的时间尺度内折叠。这些蛋白质的动力学和功能动力学将使用从大量独立模拟建立的马尔可夫状态模型来研究。与蛋白质中变构效应相关的理论将得到检验。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。该项目的一个重要内容是培训具有物理、生物学和计算方法专业知识的科学家。这种培训将针对不同教育层次的学生--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因素是致力于加强代表不足的群体对研究的参与。国际和平研究所的实验室已经并将继续接待在该小组进行研究的少数族裔和女性本科生。这些学生中的许多人现在已经获得了博士学位或正在攻读研究生学位。该项目由生物科学局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局物理部的生命系统物理学项目共同支持。

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.