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 蛋白质在其周围漫无目的地波动。为了有效地引导能量 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 编码特定功能的风景。尽管理论和计算研究具有 大大提高了我们对蛋白质能量景观的理解，现有知识是 仍然非常有限。主要概念，例如组成选择模型和等级制 能源景观（构象奴隶）模型，尚未在 原子水平。这主要是由于缺乏强大的“预测性”分子动力学抽样 可以实现足够的长时间蛋白质构象的技术 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，采样增强的数量级是合理的。 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。我们最近在自适应动态报告（ADR）方法中的创新 发展阐明了这一挑战。在这个项目中，我们将系统地发展和 在蛋白质长时间的背景下，改善这种新颖的“预测”抽样策略 动态和员工进行了开发的方法，以定量探索蛋白质大规模探索 构象动力学和破译生物物理原理的基础蛋白功能 动力学。 这项研究包括三个特定目标：（1）开发高阶正交空间温度 （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”自由能抽样； （2）理解 溶液波动在蛋白质动力学中的作用； （3）了解机械基础 人葡萄糖激酶（HGK）调节。