An adaptive compute solution for characterizing macromolecular complexes by mass spectrometry with electron-based fragmentation

一种自适应计算解决方案，用于通过基于电子的碎片质谱分析来表征大分子复合物

• 批准号: 10480227
• 负责人: Adrian Guthals
• 金额: $ 86.54万
• 依托单位: E-MSION, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480227
• 关键词: Acceleration; Address; Algorithmic Analysis; Antibodies; Arthritis; Behavior; Biological; Biological Response Modifier Therapy; COVID-19 pandemic; Cell Separation; Cells; Collection; Communities; Complex; Complex Analysis; Computer software; Computers; Cystine; Data; Data Analyses; Data Collection; Diabetes Mellitus; Diagnosis; Disease; Dissociation; Disulfides; Electronics; Electrons; Engineering; Ensure; Family; Furuncles; Goals; Grant; Heart Diseases; Intelligence; Intervention; Ions; Isoleucine; Isotopes; Judgment; Leucine; Macromolecular Complexes; Malignant Neoplasms; Manuals; Mass Spectrum Analysis; Methods; Modernization; Nerve Degeneration; Noise; Optics; Peptides; Phase; Post-Translational Protein Processing; Process; Proteins; Proteomics; Readability; Reading; Research Personnel; Resolution; Running; Safety; Sampling; Signal Transduction; Small Business Innovation Research Grant; Speed; Stream; Structure; Techniques; Technology; Time; Translating; Visualization software; Water; Work; base; beta-Aspartate; biopharmaceutical industry; blind; computerized data processing; coronavirus disease; cost; data quality; design; experience; flexibility; improved; innovation; instrument; instrumentation; interest; ion mobility; macromolecule; mass spectrometer; open source; operation; pandemic disease; parallel architecture; preservation; primary outcome; programs; protein complex; protein structure; success; tool; user-friendly

Despite two decades of advances in the speed, resolution and mass accuracy of modern mass spectrometers, the characterization and quantification of biological macromolecules remains a daunting challenge. The remaining weakness with current instrumentation lies in the methods used to fragment macromolecules, which e-MSion is addressing with an efficient electron-fragmentation technology called ExD. The exceptional sequence coverage of native proteins and preservation of labile post-translational modifications achieved with our technology is capturing the interest of the biopharma and top-down communities. Our ExD cell is the only electron-based method that can keep pace with ion mobility separations. The combination of ExD with IMS opens many opportunities to better probe protein structure and work with protein complexes. We now have strong comarketing arrangements with Agilent, Thermo and Waters for their high-end instruments and have been granted deep access to their electronics and internal data processing. Our phase I efforts focused on creating a software application called ExD Viewer that addressed user concerns about processing electron fragmentation spectra produced by our ExD technology. This software helps users to address unmet needs for probing cystine knot proteins, validating antibody sequences and characterizing proteoform more completely. One particularly well-received capability provided by ExD Viewer allows annotation of top-down spectra live from the instrument, which users use to optimize methods. We were unable to address the second of our feasibility questions because the pandemic held up delivery of our engineering sample of the Versal Adaptive Compute Acceleration Platform (ACAP) by a year. However, the Versal ACAP has become commercially available last summer. Versal is a major hardware advance that allows massive streams of real-time data to be processed at least 100-fold faster than with current CPU/GPU processors and with the potential to transform how proteomics is conducted. Our current ExD Viewer uses efficient modern programming frameworks to process complex spectra in minutes. For Phase II, we will port the backend core engine to run efficiently on the powerful Versal ACAP enabled- workstation. Accomplishing this objective will allow entire frames of ion mobility spectra (IMS-MS) to be continuously analyzed. The Versal ACAP will allow adaptive control the ExD cell and mass spectrometer to dynamically adjust data collection to more fully characterize macromolecules on the fly and to apply a broader range of tools. The commercial value comes from reducing both sample analysis time and the need for expert user input. Our primary outcome for phase II is to develop user-facing workflows that optimize the activation, fragmentation and dissociation of native proteins on the fly, enabling faster and more comprehensive characterization of challenging proteoforms important to biomedical researchers and the biopharmaceutical industry.

尽管现代质谱仪的速度、分辨率和质量精度取得了二十年的进步， 生物大分子的表征和定量仍然是一项艰巨的挑战。这 当前仪器的剩余弱点在于用于片段化大分子的方法， e-MSion 正在通过一种称为 ExD 的高效电子碎片技术来解决这个问题。这 天然蛋白质的特殊序列覆盖和不稳定翻译后修饰的保留 我们的技术所取得的成就正在引起生物制药和自上而下社区的兴趣。我们的 ExD 池是唯一能够与离子淌度分离保持同步的基于电子的方法。这 ExD 与 IMS 的结合为更好地探测蛋白质结构和合作提供了许多机会 蛋白质复合物。我们现在与 Agilent、Thermo 和 Waters 建立了强有力的联合营销安排 他们的高端仪器，并被授予对其电子设备和内部数据的深度访问权限 加工。我们第一阶段的工作重点是创建一个名为 ExD Viewer 的软件应用程序，该应用程序解决了 用户对处理我们的 ExD 技术产生的电子碎裂谱感到担忧。这 软件帮助用户解决探测胱氨酸结蛋白、验证抗体的未满足需求 序列和更完整地表征蛋白质型。一项特别受欢迎的功能 ExD Viewer 提供的功能允许从仪器实时注释自上而下的光谱，用户可以使用它来 优化方法。我们无法解决第二个可行性问题，因为大流行 Versal 自适应计算加速平台 (ACAP) 工程样品的交付被推迟 一年后。然而，Versal ACAP 已于去年夏天上市。韦尔萨尔是一个主要 硬件的进步使得海量实时数据流的处理速度至少比以前快 100 倍。 与当前的 CPU/GPU 处理器相结合，并有可能改变蛋白质组学的开展方式。我们的 当前的 ExD Viewer 使用高效的现代编程框架在几分钟内处理复杂的光谱。 对于第二阶段，我们将移植后端核心引擎，以便在启用强大的 Versal ACAP 的情况下高效运行 - 工作站。实现这一目标将使离子淌度谱 (IMS-MS) 的整个框架得以实现 不断地分析。 Versal ACAP 将允许自适应控制 ExD 单元和质谱仪 动态调整数据收集，以更全面地动态表征大分子并应用 更广泛的工具。商业价值来自于减少样品分析时间和需求 用于专家用户输入。我们第二阶段的主要成果是开发面向用户的工作流程，以优化 动态激活、裂解和解离天然蛋白质，从而实现更快、更高效 对生物医学研究人员和生物医学研究人员很重要的具有挑战性的蛋白质形式的全面表征 生物制药产业。