Theory and Modeling of Biomolecules and their Interactions

项目概要/摘要 从统计力学和计算机模拟技术的工具和方法的建立， 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， 生物医学研究这项建议要求支持我们在这一领域正在进行的努力， 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。我们提出的发展努力包括探索受体-配体 相互作用和配体结合生物受体的热力学通过持续的发展 以及自由能模拟的新方法在配体结合热力学、对接和 受体-配体相互作用模型不断完善、强化和应用理论和 恒定pH分子动力学的计算方法，以整合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 这是我们将通过拟议工作继续应对的另一项挑战。最后，软件 基础设施，特别是CHARMM大分子模拟包，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这个社区标准软件中 包.我们将平衡和推动我们在自由能模拟，配体- 受体对接和pH介导的结构-功能过程，重要的是更深层次的机制 通过与实验同事的战略合作，理解生物医学导向的问题 在以下领域：基于小的两亲分子的转录激活，其靶向来自 CREB结合蛋白（KIX）和Med 25的AciD结构域;关键的癌症靶点，如menin-MLL蛋白- 蛋白质相互作用抑制;酰基蛋白硫酯酶抑制剂，用于抗癌疗法 致癌HRas;酶的重新设计和底物范围的扩大，以更好地了解功能的演变 一种新的黄素依赖性羟化酶在利用复杂的化学转化中的重要性， 药物的开发;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;豆蔻酰化的嗜组织蛋白的pH调节开关， 在结构上与白细胞介素-1b和成纤维细胞生长因子同源。最后，我们将聘请专家参与 开发分子模拟的大数据应用程序以及设计和执行强大的用户API 与我们合作，推进软件开发的目标，以实现大型多尺度模拟细胞 环境和自动化工作流程，通过CHARMM-GUI，为复杂的模拟协议。

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.