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: 10581698
• 负责人: Adrian Guthals
• 金额: --
• 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 2023-03-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581698
• 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 Adjustments; Data Analyses; Data Collection; Diabetes Mellitus; Diagnosis; Disease; Dissociation; Disulfides; Electronics; Electrons; Engineering; Ensure; Family; Furuncles; Goals; Grant; Heart Diseases; Intelligence; Intervention; Ions; Isoleucine; Isomerism; Isotopes; Judgment; Learning; Leucine; Macromolecular Complexes; Malignant Neoplasms; Manuals; Maps; 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; 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.

尽管现代质谱仪在速度、分辨率和质量精度方面取得了二十年的进步， 生物大分子的表征和量化仍然是一个艰巨的挑战。这个 当前仪器的不足之处在于用于碎裂大分子的方法， E-MSion正在使用一种名为EXD的高效电子碎片技术来解决这一问题。这个 天然蛋白质的特殊序列覆盖率和不稳定的翻译后修饰的保存 通过我们的技术实现的是吸引生物制药和自上而下社区的兴趣。我们的 EXD电池是唯一一种可以跟上离子迁移率分离的电子方法。这个 EXD和IMS的结合为更好地探索蛋白质结构和与 蛋白质复合体。我们现在与安捷伦、Thermo和Waters达成了强有力的共同营销安排 他们的高端仪器，并已获准深入访问他们的电子产品和内部数据 正在处理。我们的第一阶段工作重点是创建一个名为EXD查看器的软件应用程序，该应用程序解决了 用户担心处理由我们的EXD技术产生的电子碎裂谱。这 软件帮助用户解决未满足的对探测胱氨酸结蛋白、验证抗体的需求 更完整的蛋白质序列和特征。一种特别受欢迎的功能 由EXD查看器提供，允许从仪器中对自上而下的光谱进行实时注释，用户可以使用该仪器 优化方法。我们无法回答第二个可行性问题，因为大流行 推迟交付我们的Versal自适应计算加速平台(ACAP)的工程样机 差了一年。然而，Versal ACAP已于去年夏天投入商业销售。Versal是一名少校 硬件进步，使处理海量实时数据流的速度至少比 利用当前的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，以便在功能强大的Versal ACAP上高效运行- 工作站。实现这一目标将允许离子迁移率谱(IMS-MS)的整个框架 持续分析。Versal ACAP将允许自适应控制EXD池和质谱计 动态调整数据收集以更充分地表征动态大分子并应用 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，以优化 在飞行中激活、裂解和解离天然蛋白质，使更快和更多 具有挑战性的蛋白形式的全面表征对生物医学研究人员和 生物制药行业。