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.

项目总结/摘要 建立统计力学和计算机模拟工具，使探索 生物分子及其相互作用是生物医学研究中发现的核心。这项建议 支持这一领域的持续努力，解决理论和建模方面的挑战，以及战略上的挑战。 在重要的生物医学问题上选择合作，为这些方法提供关键的测试。我们 开发工作包括探索受体-配体相互作用和配体热力学 通过开发和应用自由能的新方法与生物受体结合 模拟、对接和受体-配体相互作用建模。持续的精炼、硬化和 应用恒定pH分子动力学方法整合pH和质子化的关键方面 生物分子及其配体在分子模拟和建模中的状态变化也是正在进行的 工作最后，软件基础设施，特别是CHARMM模拟包，提供了框架， 推进我们的方法论，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的动机问题。我们将继续以创新的方式实施 方法和模拟方法到这个社区标准软件包。我们将平衡和驱动 我们在自由能模拟、配体-受体对接和pH介导的 通过与实验同事在以下领域的战略合作，实现结构-功能过程： 基于小的两亲分子靶向来自CREB结合的共激活物的转录激活 蛋白质（KIX）和Med 25的AciD结构域;关键的癌症靶点，如menin-MLL;酶的重新设计和 底物范围扩大，以更好地了解一种新的黄素依赖性 羟化酶，用于药物开发中重要的化学转化; pH调节 与来自四聚体Gai蛋白的G蛋白相关的激酶信号传导中的传感器; pH调节的 豆蔻酰化亲组蛋白（一种与白细胞介素-1b同源的肌动蛋白结合蛋白）与成纤维细胞生长的开关 因子最后，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，与我们一起推进大型多规模软件开发 通过CHARMM-GUI模拟蜂窝环境和自动化工作流程，以实现模拟协议。 这一要求的补充提供了一个关键的更新，以计算基础设施所需的 作为我们R35奖项的一部分提出的开发和应用。我们做出了巨大努力， 加速计算平台（GPU）上的计算算法和拟议的仪器将 支持访问这些平台中的最新版本，取代标准CPU和老化的GPU平台， 它们的使用寿命，从而促进算法开发和关键生物医学应用的生产力。