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定量仍然是一个令人生畏的挑战。的 当前仪器的剩余弱点在于用于片段化大分子的方法， e-MSion正在使用一种名为ExD的高效电子碎片技术来解决这个问题。的 天然蛋白质的特殊序列覆盖率和不稳定翻译后修饰的保留 我们的技术所取得的成就是吸引了生物制药和自上而下社区的兴趣。我们 ExD池是唯一能够与离子迁移率分离保持同步的基于电子的方法。的 ExD与IMS的结合为更好地探测蛋白质结构和与 蛋白质复合物我们现在与安捷伦、赛默和沃茨有强大的共同营销安排， 他们的高端仪器，并已获准深入访问他们的电子和内部数据 处理.我们的第一阶段工作重点是创建一个名为ExD Viewer的软件应用程序， 用户对处理我们的ExD技术产生的电子碎片光谱的担忧。这 软件可帮助用户解决探测胱氨酸结蛋白、验证抗体 序列和表征蛋白质更完整。一个特别受欢迎的能力 ExD Viewer提供的自上而下的光谱注释功能允许从仪器实时注释自上而下的光谱，用户可使用该功能 优化方法。我们无法解决第二个可行性问题， 推迟交付我们的通用自适应计算加速平台（ACAP）工程样本 一年。然而，Versal ACAP已于去年夏天上市。Versal是一个专业 硬件的进步，使大量的实时数据流的处理速度至少快100倍， 与当前的CPU/GPU处理器，并有可能改变如何进行蛋白质组学。我们 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谱（IMS-MS）的整个帧被 不断分析。Versal ACAP将允许自适应控制ExD池和质谱仪， 动态调整数据收集，以更全面地表征大分子，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要 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， 天然蛋白质的激活、片段化和解离，使其能够更快、更广泛地 具有挑战性的蛋白质型的全面表征对生物医学研究人员和 生物制药行业。