Free Energy Sampling of Long-Timescale Biomolecular Dynamics

长时标生物分子动力学的自由能采样

• 批准号: 10160921
• 负责人: Wei Yang
• 金额: $ 30.06万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-10 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160921
• 关键词: Acceleration; Algorithms; Binding Sites; Biochemical; Biological Process; Biophysics; Characteristics; Collaborations; Communities; Complex; Data; Development; Ensure; Environment; Etiology; Event; Free Energy; Glucokinase; Glucose; Goals; Human; Investigation; Kinetics; Knowledge; Light; Mathematics; Methods; Modeling; Molecular Conformation; Motion; Play; Process; Protein Conformation; Protein Dynamics; Proteins; Regulation; Reporting; Role; Sampling; Scheme; Slave; Structure; System; Techniques; Theoretical Studies; Water; base; biophysical analysis; computer studies; design; drug discovery; experimental study; improved; innovation; method development; millisecond; molecular dynamics; novel; protein function; response; simulation

Project Summary Protein aimlessly fluctuates in its surrounding. In order for energy to be effectively channeled through the complex interaction network and so accurately activate essential transitions, often hundreds of microseconds, to milliseconds, even to tens of seconds of dynamics are required. Several decades’ biophysical studies suggest that proteins likely possess characteristic energy landscapes that encode specific functions. Although theoretical and computational studies have greatly improved our understanding on protein energy landscape, the existing knowledge is still very limited. Dominant concepts, such as conformation selection model and hierarchical energy landscape (conformational slaving) model, have not been adequately understood at the atomistic level. This is largely due to lack of robust “predictive” molecular dynamics sampling technique that can enable adequate exploration of long-timescale protein conformational changes. The orthogonal space sampling (OSS) scheme, particularly its high order generalization, allows for systematic acceleration of energy flow as required for thorough sampling enhancement. Preliminary studies suggest that orders of magnitude of sampling enhancement are plausible. However a major challenge for OSS has been lack of rigorous algorithmic solution to ensure sampling robustness. Our recent innovation in the adaptive dynamic reporting (ADR) method development sheds light on this challenge. In this project, we will systematically develop and improve this novel “predictive” sampling strategy in the context of protein long-timescale dynamics and employ to-be-developed methods to quantitatively explore protein large-scale conformational dynamics and decipher biophysical principles underlying protein functional dynamics. This study includes three specific goals: (1) Developing high order orthogonal space tempering (HOOST) method based on the adaptive dynamic reporting (ADR) kernel to enable robust “predictive” free energy sampling of biomolecular long-timescale dynamics; (2) Understanding roles of solvation fluctuation in protein dynamics; (3) Understanding the mechanistic basis of human Glucokinase (hGK) regulation.

项目摘要 蛋白质漫无目的的波动是周围的。 通过复杂的相互作用网络，因此经常激活基本过渡 数百微秒至毫秒至毫秒，甚至需要数十秒的动力学。 几十年的生物物理研究表明蛋白质可能具有特征能量 编码特定功能的景观。 大大提高了我们对蛋白质能量景观的理解，去sting知识是 仍然非常有限。 能源景观（构象奴隶）模型，在你的理解还不够 原子水平。这是由于缺乏强大的“预测性”分子动力学 可以实现足够的长时间蛋白profmental的技术 更改。 正交空间采样（OSS）方案，尤其是其高阶概括，允许 为了系统地加速能量流，需要进行彻底的采样增强。 初步研究表明，采样增强的采样顺序是合理的。 但是，OSS的主要挑战是缺乏严格的算法解决方案来确保 采样鲁棒性。 开发阐明了这个项目中的挑战。 在蛋白质长时间的背景下，改善这种新颖的“预测”抽样策略 动力学和采用型的方法来定量探索蛋白质大规模的蛋白质 构象动力学和破译生物物理原理的基础蛋白质功能 动力学。 这项研究包括三个具体目标：（1）开发高阶正交空间回火 （HOOST）基于自适应动态报告（ADR）内核的方法以启用鲁棒 生物分子长时间动力学的“预测性”自由能采样； 溶液在蛋白质动力学中的作用；（3） 人葡萄糖激酶（HGK）调节。