Achieving Long Timescale Sampling in Biomolecular Simulations

在生物分子模拟中实现长时间尺度采样

• 批准号: 0919983
• 负责人: Wei Yang
• 金额: $ 44.36万
• 依托单位: Florida State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0919983&HistoricalAwards=false
• 关键词: Achieving; Long; Timescale; Sampling; Biomolecular

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).The objective of this research is to develop and apply efficient simulation methods to quantitatively describe complex biomolecular phenomena that usually occur in longer timescale than what conventional methods can achieve. Molecular recognition such as protein-ligand recognition and large conformational transition are two key elements in biomolecular machines. Due to timescale limitation, quantitative understanding of these events via computer simulation has been very challenging. In this project, efficient generalized ensemble simulation methods will be developed and employed to enhance the sampling power of biomolecular simulations. The promise of this project is particularly ensured by a recent methodological development in the PI's lab: the orthogonal space random walk (OSRW) algorithm, which can uniquely realize collective environmental relaxation in a robust and efficient manner. Specifically, three aims will be targeted: (1) understanding protein-protein interactions and protein electrostatics via OSRW based free energy simulations; (2) developing a hybrid quantum mechanical/molecular mechanical (QM/MM) based OSRW sampling scheme to more accurately describe protein-ligand interactions; (3) developing OSRW based conformational sampling methods to predict protein functional dynamics. In recent years, the PI has made tremendous efforts in organizing workshops and meetings to connect computational biophysics and experimental biophysics and to bridge method developments and biological applications. Some of these workshops, for instance, Telluride workshop on sampling enhancement, have become standing ones. In particular, the PI has been putting enormous emphasis in building multi-layered environments for young scientists so that they can receive suitable education to carry out multi-disciplinary research. In order for the advanced methods that are recently developed in the groups of PI and others to be quickly absorbed by the scientific community, the PI edited a special issue on free energy simulation in Journal of Computational Chemistry in early 2009 and is co-writing a book that is focused on modern simulation methods and their hand-on application. In addition, the developed methods through this project will be released in the program CHARMM, which can be widely employed by general scientific community.

该奖项是根据2009年的《美国回收与再投资法》（公法111-5）资助的。这项研究的目的是开发和应用有效的仿真方法来定量描述通常在更长时间范围内发生的复杂生物分子现象，而这些现象通常比常规方法实现的时间更长。分子识别（例如蛋白质 - 配体识别和较大的构象过渡）是生物分子机器中的两个关键要素。由于时间尺度的限制，通过计算机模拟对这些事件的定量理解非常具有挑战性。在这个项目中，将开发和使用有效的广义集合模拟方法来增强生物分子模拟的采样能力。 PI的实验室中的最新方法论发展尤其确保了该项目的承诺：正交空间随机步行（OSRW）算法，该算法可以独特地以强大而有效的方式实现集体环境放松。具体而言，将针对三个目标：（1）通过基于OSRW的自由能模拟了解蛋白质 - 蛋白质相互作用和蛋白质静电； （2）开发基于杂种量子机械/分子机械（QM/mm）的OSRW采样方案，以更准确地描述蛋白质 - 配体相互作用； （3）开发基于OSRW的构象采样方法来预测蛋白质功能动力学。近年来，PI在组织研讨会和会议上做出了巨大的努力，以连接计算生物物理学和实验生物物理学，并桥接方法的开发和生物学应用。例如，其中一些研讨会关于提高采样的泰篇研究研讨会已成为站立的研讨会。特别是，PI一直在为年轻科学家建立多层环境，以便他们可以接受合适的教育以进行多学科研究。为了使PI组最近开发的高级方法和其他人很快被科学界吸收，PI编辑了2009年初的《计算化学杂志》中关于自由能模拟的特刊，并共同编写了一本专注于现代仿真方法及其手工应用的书。此外，通过该项目开发的方法将在CHARMM计划中发布，该计划可以由一般科学界广泛使用。