Theory and Modeling of Biomolecules and their Interactions - Equipment Supplement

生物分子及其相互作用的理论和建模 - 设备补充

• 批准号: 10580491
• 负责人: CHARLES L BROOKS
• 金额: $ 22.1万
• 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/10580491
• 关键词: Acids; Actin-Binding Protein; Address; Aging; Area; Award; Big Data; Biological; Biomedical Research; CREBBP gene; Chemicals; Collaborations; Communities; Computational algorithm; Computer Simulation; Computer software; Development; Docking; Environment; Enzymes; Equilibrium; Equipment; Evolution; Fibroblast Growth Factor; Flavins; Free Energy; GTP-Binding Proteins; Genetic Transcription; Goals; Homologous Protein; Interleukins; Ligand Binding; Ligands; Longevity; MED25 gene; Malignant Neoplasms; Maps; Mediating; Mediation; Menin; Methodology; Methods; Mixed Function Oxygenases; Modeling; Molecular; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Process; Productivity; Proteins; Protocols documentation; Research; Signal Transduction; Statistical Mechanics; Structure; Testing; Thermodynamics; Transcriptional Activation; Update; Work; algorithm development; base; computational platform; computer infrastructure; design; innovation; insight; instrumentation; interdisciplinary approach; models and simulation; molecular dynamics; novel; protonation; receptor; sensor; simulation; small molecule; software development; software infrastructure; theories; tool

Project Summary/Abstract The establishment of tools from statistical mechanics and computer simulation that enable the exploration of biological molecules and their interactions are central to discovery within biomedical research. This proposal supports ongoing efforts in this area, addressing challenges in theory and modeling, as well as strategically chosen collaborations on important biomedical questions that provide crucial tests of the approaches. Our development efforts include the exploration of receptor-ligand interactions and the thermodynamics of ligand binding to biological receptors through the development and application of novel methods of free energy simulations, docking and receptor-ligand interaction modeling. The continued refinement, hardening and application of methods of constant pH molecular dynamics to integrate the critical aspects of pH and protonation state changes in biomolecules and their ligands in molecular simulations and modeling is also part of ongoing work. Finally, software infrastructure, specifically the CHARMM 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. We will 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 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; enzyme redesign and substrate scope expansion to better understand the evolution of function of a novel Flavin-dependent hydroxylase for 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, an actin binding protein homolog with interleukin-1b and fibroblast growth factor. Finally, we will engage developers of big data applications of molecular simulations and the design and execution of robust user APIs to work with us toward advancing software development for large multi-scale simulations of cellular environments and automated workflows, through CHARMM-GUI, for simulation protocols. This requested supplement provides a critical update to the computational infrastructure needed for the developments and applications proposed as part of our R35 award. We have made significant efforts to map computational algorithms onto accelerated computing platforms (GPUs) and the proposed instrumentation will enable access to the latest of these platforms, replacing standard CPU and aging GPU platforms that are beyond their useful lifespan, thus facilitating the productivity of algorithm development and key biomedical applications.

项目摘要/摘要 从统计力学和计算机模拟中建立工具，以探索 生物学分子及其相互作用在生物医学研究中是发现的核心。这个建议 支持该领域正在进行的努力，解决理论和建模的挑战，并在战略上进行 选择有关重要生物医学问题的合作，以提供对方法的关键测试。我们的 开发工作包括探索接收器配体相互作用和配体的热力学 通过开发和应用新颖的自由能方法结合生物受体 仿真，对接和接收器配体相互作用建模。持续的完善，硬化和 恒定pH分子动力学方法的应用以整合pH和质子化的关键方面 分子模拟中生物分子及其配体的状态变化也是正在进行的一部分 工作。最后，软件基础架构，特别是Charmm仿真软件包，为 推进我们的方法论方法，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发来激发问题。我们将继续进行创新的实施 方法和仿真方法进入了这个社区标准软件包。我们将平衡和开车 我们在自由能模拟，配体 - 受体对接和pH介导的领域的开发工作 结构功能通过战略合作与在以下领域的实验合作进行： 基于针对CREB结合的靶向共激活剂的小两亲分子的转录激活 蛋白质（Kix）和Med25的酸性域；关键癌症靶标，例如Menin-Mll；酶重新设计和 底物范围扩展，以更好地理解新黄素依赖性功能的功能演变 化学转化的羟化酶对药物开发很重要； pH调节 与四聚体GAI蛋白的G蛋白相关的激酶信号传导中的传感器； pH调节 开关的肉豆蔻酰化的组织分裂蛋白，肌动蛋白结合蛋白同源物具有白介素1b和成纤维细胞生长 因素。最后，我们将吸引分子模拟和设计的大数据应用程序的开发人员 执行强大的用户API，以与我们合作，以推进大型多尺度的软件开发 通过CHARMM-GUI对蜂窝环境和自动工作流进行仿真方案的模拟。 此请求的补充提供了对该计算基础架构的关键更新 作为我们R35奖的一部分，提议的开发和申请。我们已经做出了巨大的努力 加速计算平台（GPU）和拟议仪器的计算算法将 启用最新平台，替换超出超越的标准CPU和老化的GPU平台 它们有用的寿命，从而支持算法开发和关键生物医学应用的生产率。