Computational Studies of Folding and Dynamics of Proteins

蛋白质折叠成其天然结构的机制是生物学中一个重要的研究课题。蛋白质在细胞中执行大部分分子水平的功能。此外，蛋白质是纳米级分子机器，可以执行生物技术应用的重要任务。众所周知，蛋白质的边际稳定性可以通过改变溶剂条件而改变，例如施加压力或添加助溶剂。计算机模拟可以在原子水平上描述溶剂（主要是水）、助溶剂和物理效应（如压力和温度）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使蛋白质折叠/展开平衡和动力学的研究成为可能。本项目旨在研究复杂程度增加的模型蛋白的折叠/展开平衡和动力学。模拟将探索助溶剂和静水压力对过渡态的影响，并将有助于理解溶剂在决定蛋白质过渡态方面的作用，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上折叠的模型蛋白质上完成，并且有充足的动力学和热力学实验数据可用。除了折叠之外，该项目还将探索蛋白质的功能动力学——也就是说，将能量格局中存在的子状态与蛋白质的功能状态联系起来。总体目标是研究平衡折叠/展开，能量景观，折叠动力学和蛋白质相互作用和切换中涉及的蛋白质结构域的动力学。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由大量独立模拟建立的马尔可夫状态模型进行研究。与蛋白质的变构效应有关的理论将被检验。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。该项目的一个重要组成部分是培训具有物理学、生物学和计算方法专业知识的科学家。这项培训将在不同教育水平的学生中进行，包括高中生、本科生和研究生，以及博士后。这项研究的另一个同样重要的因素是承诺加强代表性不足的群体参与研究。PI的实验室一直并将继续接待在该小组进行研究的少数民族和女性本科生。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课程。该项目由生物科学理事会分子与细胞生物科学部的分子生物物理学和数学与物理科学理事会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.