Conformational dynamics, reaction coordinates, and time scale separation in biomolecular systems from the perspective of energy flows

伊利诺伊大学芝加哥分校（UIC）的Ao Ma获得了化学系化学理论、模型和计算方法项目的奖励，他开发了新的理论和计算方法，用于理解蛋白质形状随时间变化的机制，因为它与细胞中的其他分子移动和相互作用。构象变化是蛋白质功能的关键，了解复杂的蛋白质动力学对于开发新药设计策略和减轻基因组缺陷对人类健康的影响至关重要。标准的分子动力学模拟提供了在原子水平上蛋白质构象变化的细粒度信息，但目前缺乏从这些详细信息推断总体机制的系统方法。在这个项目中，正在开发新的方法，通过检查系统中随时间的能量流动，从模拟数据中严格提取蛋白质构象变化的机制。这些方法正在一系列日益复杂的系统中得到应用和测试，从小肽到与小分子（配体）相互作用的蛋白质，再到溶液中的蛋白质。为这个项目开发的计算机程序现正供公众下载。马教授通过伊利诺伊州数学与科学学院（IMSA）学生探究与研究（SIR）项目为高中生提供研究经验，以激发学生对科学和研究的热情和兴趣。除了在UIC（一个为西班牙裔服务的机构）指导和教育学生外，马教授还通过UIC正在进行的教育计划，为当地高中科学教师提供每年夏季的研究经验。这项工作的目的是发展新的理论和计算方法，以促进对功能重要的蛋白质动力学的理解。反应坐标和时间尺度分离是理解蛋白质构象动力学机制的重要概念。近年来在蛋白质动力学研究中出现的重要组织原理包括集体变量、配体诱导构象变化和溶剂奴役。这个项目从能量流动的角度对这些概念进行了形式化和统一。核心假设是，在强耦合坐标中，能量在蛋白质构象变化过程中从快速坐标流向慢速坐标。因此，反应坐标对应于首选通道，每个通道都表现出高度的能量流。有三个具体目标：1)了解作为反应坐标的集体变量如何在激活过程中出现的机制；2)确定决定配体及其周围蛋白质基质运动相对时间尺度的机制因素；3)阐明决定溶质坐标和集体溶剂模式相对时间尺度的机制因素。这些目标正在通过一系列日益复杂的生化问题进行研究：溶液中的十丙氨酸，溶剂化HIV-1蛋白酶在抑制剂存在下的构象变化，配体与视紫红质和肌红蛋白的相互作用，以及氨基酸点突变对肌红蛋白动力学的影响。为这个项目开发的代码可供公众下载。马教授正在为当地高中生提供研究经验和项目指导，以激发他们对科学和研究的热情和兴趣，并为高中科学教师提供每年夏季的实验室研究经验，并得到正在进行的UIC教育计划的支持。在这个项目中发展的见解被整合到马教授的研究生课程中，作为UIC生物信息学博士课程的一部分，这是美国为数不多的这样的项目之一

Ao Ma of the University of Illinois at Chicago (UIC) is supported by an award from the Chemical Theory, Models and Computational Methods Program in the Division of Chemistry to develop new theoretical and computational methods for understanding the mechanisms by which the shape of a protein morphs over time, as it moves and interacts with other molecules in the cell. Conformational changes are key to protein function, and understanding complex protein dynamics is essential to developing design strategies for new drugs and mitigating the impact of genomic defects on human health. Standard molecular dynamical simulations provide fine-grained information on protein conformational changes at the atomic level, but systematic methods for deducing overall mechanisms from this detailed information are currently lacking. In this project, new methods are being developed to rigorously extract mechanisms of protein conformational change from simulation data, by examining the flow of energy in the system over time. These methods are being applied and tested in a series of increasingly complex systems ranging from small peptides, to proteins interacting with a small molecule (ligand), and proteins in solution. Computer programs developed for this project are being made available for public download. Professor Ma is providing research experiences for high school students through the Illinois Mathematics and Science Academy (IMSA) Student Inquiry and Research (SIR) program, to stimulate enthusiasm and interest in science and research. In addition to mentoring and educating students at UIC, a Hispanic-Serving institution, Professor Ma provides an annual summer research experience to local high school science teachers, through an ongoing UIC educational program.The objective of this work is to develop novel theoretical and computational methods for advancing understanding of functionally-important protein dynamics. Reaction coordinates and time scale separation are fundamental concepts crucial to understanding mechanisms of protein conformational dynamics. Important organizing principles that have emerged in recent years from studies of protein dynamics include collective variables, ligand-induced conformational change, and solvent slaving. This project is formalizing and unifying these concepts from the perspective of energy flows. The central hypothesis is that, among strongly coupled coordinates, energy flows from fast coordinates into slow ones during a protein conformational change. Thus, reaction coordinates correspond to preferred channels, each exhibiting a high degree of energy flow. There are three specific aims: 1) Understand the mechanism of how a collective variable as reaction coordinate emerges in an activated process; 2) identify the mechanistic factors that determine relative time scales of the motions of a ligand and its surrounding protein matrix; and 3) clarify the mechanistic factors that determine relative time scales of solute coordinates and collective solvent modes. These aims are being investigated through a succession of increasingly complex biochemical problems: deca-alanine in solution, conformational changes in solvated HIV-1 protease in the presence of an inhibitor, ligand interactions with rhodopsin and myoglobin, and the effect of amino acid point mutations on myoglobin kinetics. Code developed for this project is being made available for public download. Professor Ma is providing research experiences and project mentoring for local high school students, to stimulate enthusiasm and interest in science and research, and an annual summer research experience in his laboratory for high school science teachers, supported by an ongoing UIC educational program. The insights developed in this project are being integrated into graduate courses taught by Professor Ma as part of the PhD program in Bioinformatics at UIC, one of just a few such programs in the U.S.