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.

尽管在现代质谱仪的速度，分辨率和质量准确性方面取得了二十年的进步，但 生物大分子的表征和定量仍然是一个艰巨的挑战。这 当前仪器的剩余无力在于用于碎片大分子的方法， 哪种电子措施正在使用一种有效的电子碎片技术来解决，称为EXD。这 天然蛋白质的特殊顺序覆盖范围和不稳定后翻译后修饰的保存 通过我们的技术实现的目的是捕捉生物制药和自上而下的社区的兴趣。我们的 EXD细胞是唯一可以与离子迁移率分离保持同步的唯一基于电子的方法。这 EXD与IMS的组合为更好的探测蛋白质结构和合作提供了许多机会 蛋白质复合物。现在，我们与安捷伦，热水和水域进行了牢固的漫步安排 他们的高端仪器，并已被授予深入访问其电子和内部数据 加工。我们的第一阶段努力专注于创建一个称为EXD查看器的软件应用程序，该应用程序解决了 用户担心我们的EXD技术生产的电子碎片光谱。这 软件可帮助用户满足探测胱氨酸结蛋白的未满足需求，从而验证抗体 序列和更完整地表征蛋白质成型。一个特别受欢迎的能力 EXD查看器提供 优化方法。我们无法解决我们的第二个可行性问题，因为大流行 持有我们的工程样本的传送样本 一年。但是，去年夏天，Versal ACAP已成为商业上。 Versal是主要的 硬件进步允许大量的实时数据流的处理速度至少比 使用当前的CPU/GPU处理器，并有可能改变蛋白质组学的进行方式。我们的 当前的EXD查看器使用有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发动机在功能强大的Versal ACAP上有效运行 - 工作站。实现此目标将使整个离子移动光谱（IMS-MS）成为 连续分析。 Versal ACAP将允许自适应控制EXD细胞和质谱仪到达 动态调整数据收集以更充分地表征大分子的即时表征 更广泛的工具。商业价值来自减少样本分析时间和需求 用于专家用户输入。我们第二阶段的主要结果是开发面向用户的工作流以优化 天然蛋白的激活，分裂和分离，使得能够更快，更快 对生物医学研究人员和 生物制药行业。