Theory and Modeling of Biomolecules and their Interactions - Equipment Supplement

项目摘要/摘要 来自统计力学和计算机模拟的工具的建立，使得能够探索 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 支持这一领域正在进行的努力，解决理论和模型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。我们的 开发工作包括探索受体-配体相互作用和配体的热力学 通过开发和应用新的自由能方法与生物受体结合 模拟、对接和受体-配体相互作用建模。持续的细化、硬化和 恒pH分子动力学方法在整合pH与质子化临界问题中的应用 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，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。我们将继续创新实施 方法和模拟方法整合到这个社区标准软件包中。我们将平衡和推动 我们在自由能模拟、配体-受体对接和pH调节领域的发展努力 通过与实验同事在以下领域进行战略协作，建立结构-功能流程： 基于CREB结合的两亲小分子靶向辅活化子的转录激活 蛋白质(KIX)和Med25的酸性结构域；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理解新的黄素依赖功能的进化 在药物开发中起重要作用的化学转化的羟基酶；pH调节 与来自四聚体Gai蛋白的G蛋白相关的激酶信号感受器；pH调节的 一种肌动蛋白结合蛋白，与白细胞介素1b和成纤维细胞生长同源 因素。最后，我们将邀请分子模拟的大数据应用程序的开发人员，并设计和 执行强大的用户API，与我们合作推进大型多规模的软件开发 通过CHARMM-图形用户界面模拟蜂窝环境和自动化工作流程，用于模拟协议。 这一要求的补充提供了计算基础设施的关键更新 作为我们R35奖项的一部分，建议的开发和应用。我们已经做出了重大努力来绘制 加速计算平台(GPU)上的计算算法和建议的工具将 支持访问这些平台中的最新平台，取代超越标准CPU和老化的GPU平台 它们的使用寿命，从而促进了算法开发和关键生物医学应用的生产力。

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.