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.

项目摘要/摘要 建立从统计力学到计算机模拟技术的工具和方法 能够探索生物分子及其相互作用在发现中起着核心作用 生物医学研究。这项建议是请求支持我们在这一领域正在进行的努力，并 还包括解决与这些问题相关的理论和模型方面的挑战的目标 作为战略性选择的合作，将有助于阐明重要的生物医学问题并提供关键的 对我们开发的方法进行测试。我们建议的开发工作包括探索受体配体 生物受体与配体的相互作用和热力学研究进展 并将自由能模拟的新方法应用于配体结合热力学、对接和 受体-配体相互作用模型。理论和实践的不断完善、强化和应用 整合pH与质子化临界点的恒pH分子动力学计算方法 蛋白质和核酸受体及其配体在分子模拟和模拟中的状态变化 这是我们将继续通过拟议工作应对的另一项挑战。最后，软件 基础设施，特别是CHARMM大分子模拟包，为 推进我们的方法学方法，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，激发了问题的积极性。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应用到该社区标准软件中 包裹。我们将平衡和推动我们在自由能源模拟、配体- 受体对接和pH介导的结构-功能过程，对更深层次的机制很重要 通过与实验同事的战略性合作，理解生物医学指导的问题 在以下领域：基于小分子两亲性分子的转录激活作用 CREB结合蛋白(KIX)和Med25的酸性结构域；关键的癌症靶点，如Menin-MLL蛋白- 蛋白质相互作用抑制；用于抗癌治疗的酰基蛋白质硫代酯酶抑制剂 致癌的HRAs；酶的重新设计和底物范围的扩大以更好地了解功能的进化 一种新的黄素依赖羟基酶在开发复杂的化学转化中的作用 药物的开发；与G蛋白相关的激酶信号中的pH调节传感器 四聚体GAI蛋白；肌动蛋白结合蛋白，是肉豆蔻酰化的组氨酸的pH调节开关。 在结构上与白介素1b和成纤维细胞生长因子同源。最后，我们将邀请专家参与 分子模拟大数据应用程序的开发和健壮用户API的设计与执行 与我们共同努力，推进细胞大规模多尺度模拟软件开发的目标 环境和自动化工作流程，通过CHARMM-图形用户界面，实现复杂的模拟协议。