Achieving Long Timescale Sampling in Biomolecular Simulations

摘要：科学价值：长时间尺度的构象波动可能导致蛋白质的异常静电效应和酶反应的远程调节。由于时间尺度的限制，通过计算机模拟来准确理解这些事件一直是非常具有挑战性的。这项研究的目标是开发和应用新的分子动力学模拟方法来定量描述复杂的生物分子现象，这些现象通常发生在比传统技术所能实现的更长的时间尺度上。在这个项目中，将开发和使用专门的计算机模拟算法来提高生物分子模拟的采样能力。具体地说，主要目标将在两个重点领域完成：(1)蛋白质静电效应的定量预测及其与蛋白质构象转变的耦合；(2)了解缓慢的酶波动如何准备独特的催化环境来激活化学反应。这些研究将提供对蛋白质构象变化在关键生物过程中所起作用的更深层次的理解。广泛的影响：正在开发的计算机模拟方法将分发给普通科学界。一些特定的算法很有可能成为相关研究领域的主要技术。这项研究的成功将激励生物分子模拟领域中更多面向问题的抽样设计努力。与科学项目相配合，将进一步开发一门专门的研究生课程“生物学的时间尺度和长度尺度”。作者将继续组织国家和国际会议和讲习班，以激励和促进年轻一代科学家在定量计算生物物理学方面的教育。本科生和高中生将继续努力参与这项研究，使用计算机模拟来探索蛋白质的结构、动力学和功能。

Abstract:Scientific merit: Long timescale conformational fluctuations can be responsible for unusual protein electrostatic effects and remote modulation of enzymatic reactions. Due to the timescale limitation, accurate understanding of these events via computer simulation has been very challenging. The goal of this research is to develop and apply novel molecular dynamics simulation methods to quantitatively describe complex biomolecular phenomena that usually occur in much longer timescales than what conventional techniques can achieve. In this project, specialized computer simulation algorithms will be developed and employed to enhance the sampling power of biomolecular simulations. Specifically, the main objectives will be accomplished in two focused areas: (1) Quantitative prediction of protein electrostatic effects and understanding their coupling with protein conformational transitions; (2) Understanding how slow enzyme fluctuations prepare unique catalytic environments to activate chemical reactions. These studies will provide deeper understanding of the roles that protein conformational changes play in key biological processes.Broader impacts: The computer simulation methods under development will be distributed to general scientific community. Some specific algorithms will very possibly become major techniques in related research areas. The success of this research will motivate more problem-oriented sampling design efforts in the field of biomolecular simulation. Synergistic with the scientific project, a special graduate course "Time-scale and Length-scale in Biology" will be further developed. National and international meetings and workshops will continue to be organized by the author to motivate and catalyze the education of younger-generation scientists on the subject of quantitative computational biophysics. Efforts will continue in the involvement of undergraduate students and high school students in this research, using computer simulations to explore protein structures, dynamics, and functions.