Theory and Modeling of Biomolecules and their Interactions

生物分子及其相互作用的理论和建模

• 批准号: 10094219
• 负责人: CHARLES L BROOKS
• 金额: $ 83.16万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094219
• 关键词: Acids; Actin-Binding Protein; Address; Area; Big Data; Biological; Biomedical Research; CREBBP gene; Chemicals; Collaborations; Communities; Complex; Computer Simulation; Computer software; Computing Methodologies; Development; Docking; Environment; Enzymes; Equilibrium; Evolution; Fibroblast Growth Factor; Flavins; Free Energy; GTP-Binding Proteins; Genetic Transcription; Goals; HRX protein; Interleukins; Ligand Binding; Ligands; MED25 gene; Malignant Neoplasms; Mediating; Mediation; Menin; Methodology; Methods; Mixed Function Oxygenases; Modeling; Molecular; Nucleic Acids; Oncogenic; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Play; Process; Proteins; Protocols documentation; Research; Role; Signal Transduction; Statistical Mechanics; Statistical Methods; Structure; Technology; Testing; Thermodynamics; Transcriptional Activation; Work; base; cancer therapy; design; inhibitor/antagonist; innovation; insight; models and simulation; molecular dynamics; novel; protein protein interaction; protonation; receptor; sensor; simulation; small molecule; software development; software infrastructure; theories; tool

Project Summary/Abstract The establishment of tools and methods from statistical mechanics and computer simulation technology to enable the exploration of biological molecules and their interactions plays a central role in discovery within biomedical research. This proposal represents a request for support of our ongoing efforts in this area and includes objectives to address challenges in the theory and modeling associated with these problems, as well as strategically chosen collaborations that will help elucidate important biomedical questions and provide crucial tests of the approaches we develop. Our proposed development efforts include the exploration of receptor-ligand interactions and the thermodynamics of ligand binding to biological receptors through the continued development and application of novel methods of free energy simulations to ligand binding thermodynamics, docking and receptor-ligand interaction modeling. The continued refinement, hardening and application of theoretical and computational methods of constant pH molecular dynamics to integrate the critical aspects of pH and protonation state changes in protein and nucleic acid receptors and their ligands in molecular simulations and modeling represents another challenge we will continue to address with the proposed work. Finally, software infrastructure, specifically the CHARMM macromolecular simulation package, provides the framework for advancing our methodological approaches and enabling the broader community to explore biomedically motivated questions via its wide usage and distribution. A component of our proposed efforts will be to continue the innovative implementation of methods and simulation approaches into this community standard software package. We will balance and drive our development efforts in the areas of free energy simulations, ligand – receptor docking and pH-mediated structure-function processes, important to a deeper mechanistic understanding of biomedically directed questions, through strategic collaborations with experimental colleagues in the areas of: transcriptional activation based on small amphipathic molecules targeting co-activators from the CREB binding protein (KIX) and the AciD domain of Med25; key cancer targets such as menin-MLL protein- protein interaction inhibition; inhibitors of acyl protein thioesterases, targeted in anti-cancer therapies for oncogenic HRas; enzyme redesign and substrate scope expansion to better understand the evolution of function of a novel Flavin-dependent hydroxylase in exploiting complex chemical transformations important in the development of pharmaceuticals; pH-regulated sensors in kinase signaling associated with the G-protein from the tetrameric Gai protein; the pH-modulated switch for myristoylated histactophilin, the actin binding protein that is structurally homologous with interleukin-1b and fibroblast growth factor. Finally, we will engage experts in the development of big data applications of molecular simulations and the design and execution of robust user APIs to work with us toward advancing objectives in software development for large multi-scale simulations of cellular environments and automated workflows, through CHARMM-GUI, for sophisticated simulation protocols.

项目概要/摘要 从统计力学和计算机模拟技术出发建立工具和方法 使生物分子及其相互作用的探索在发现中发挥着核心作用 生物医学研究。该提案代表了对我们在该领域持续努力的支持的请求， 包括解决与这些问题相关的理论和建模挑战的目标，以及 作为战略选择的合作，将有助于阐明重要的生物医学问题并提供关键的 测试我们开发的方法。我们提出的开发工作包括探索受体-配体 通过持续发展，配体与生物受体结合的相互作用和热力学 以及自由能模拟新方法在配体结合热力学、对接和应用中的应用 受体-配体相互作用建模。理论和实践的不断完善、强化和应用 恒定 pH 分子动力学的计算方法，整合 pH 和质子化的关键方面 分子模拟和建模中蛋白质和核酸受体及其配体的状态变化 这是我们将继续通过拟议工作解决的另一个挑战。最后是软件 基础设施，特别是 CHARMM 大分子模拟软件包，提供了框架 推进我们的方法论并使更广泛的社区能够探索生物医学 通过其广泛的使用和分布激发了问题。我们提议的努力的一个组成部分将是继续 将方法和模拟方法创新地实施到该社区标准软件中 包裹。我们将平衡并推动我们在自由能模拟、配体领域的开发工作—— 受体对接和 pH 介导的结构功能过程，对于更深层次的机制很重要 通过与实验同事的战略合作来理解生物医学导向的问题 在以下领域：基于小两亲分子的转录激活，靶向来自 CREB结合蛋白（KIX）和Med25的AciD结构域；关键癌症靶标，例如 menin-MLL 蛋白- 蛋白质相互作用抑制；酰基蛋白硫酯酶抑制剂，针对癌症治疗 致癌HRAs；酶重新设计和底物范围扩展，以更好地理解功能的进化 一种新型黄素依赖性羟化酶在利用复杂的化学转化方面具有重要意义 药品开发；与 G 蛋白相关的激酶信号传导中的 pH 调节传感器 四聚体 Gai 蛋白；肉豆蔻酰化亲组织蛋白（一种肌动蛋白结合蛋白）的 pH 调节开关 与白细胞介素 1b 和成纤维细胞生长因子在结构上同源。最后，我们将聘请相关领域的专家 分子模拟大数据应用的开发以及强大的用户 API 的设计和执行 与我们合作，推进大规模多尺度细胞模拟软件开发目标 环境和自动化工作流程，通过 CHARMM-GUI，实现复杂的模拟协议。