High resolution cyclic ion mobility HDX mass spectrometry of protein dynamics and function

该提议是在曼彻斯特大学启用循环离子迁移率氢氘交换质谱（循环IMS HDX-MS）。该竞标旨在提高高质量HDX-MS分析日益复杂和异质生物样品的能力，这些样品在很大程度上难以通过其他生物物理和生化方法进行分析。它还将支持细胞生物学、结构化学和分子医学之间的世界级研究，这些研究对人类健康和疾病有直接影响。该仪器将使我们能够以高分辨率测量氢与重氘的交换，从而直接了解蛋白质如何移动并与其他生物分子相互作用。在过去的几年中，PI率先使用新兴的HDX-MS研究具有挑战性的膜蛋白及其与周围环境的相互作用。因此，PI不仅在英国，而且在全球范围内都处于领导这一竞标的最佳位置。该仪器将使研究达到一个全新的水平，目标是在它们生活和功能的自然环境中复杂和越来越大的生物系统。这将为理解支持案例中概述的众多疾病的机制开辟方向。这台HDX-MS仪器将被安置在曼彻斯特生物技术研究所（MIB）和迈克尔·巴伯协作质谱中心。MIB是来自科学与工程学院（FSE）和生物、医学和健康学院（FBMH）的研究小组的所在地。该仪器将由FSE和FBMH的研究小组以及学术界和工业界的外部合作者使用。它将为曼彻斯特大学内外的跨学科合作网络奠定基础。我们将使用这种最先进的设备来支持MRC的投资，并与工业合作伙伴（例如OMass Therapeutics， Waters Corp., BioShape Ltd ., AstraZeneca, FujiDiosynth）合作。新仪器将提高在其原生细胞环境中研究具有挑战性的生物系统的能力和能力。它将提供无与伦比的灵敏度，采集速度和分辨率，绕过当前技术的限制。这将使更广泛的研究途径和更广泛的应用于许多生物过程，如膜运输、药物开发和设计、催化、大分子机器和相关疾病，如癌症、结核病、心力衰竭和抗菌素耐药性。这将进一步提供在人类样本及其原生环境中进行研究的能力。

This proposal is to enable cyclic ion mobility hydrogen deuterium exchange mass spectrometry (cyclic IMS HDX-MS) at the University of Manchester. The bid aims to increase capacity and capability for high-quality HDX-MS analysis of increasingly complex and heterogeneous biological samples, largely intractable by other biophysical and biochemical methods. It will also support world-class research at the interface between cellular biology, structural chemistry and molecular medicine with direct implications into human health and disease. The instrumentation will allow us to measure the exchange of hydrogen for heavier deuterium at high resolution enabling direct insights into how proteins move and interact with other biomolecules.Over the past few years, the PI has pioneered the study of challenging membrane proteins and their interactions with their surrounding environment using emerging HDX-MS. As such the PI is at the best place o lead this bid not only in the UK but also worldwide. The instrumentation will allow taking the research to an entirely new level by targeting complex and increasingly larger biological systems in the native environment where they live and function. This will open up directions in understanding the mechanism of a multitude of diseases outlined in the case for support.This HDX-MS instrument will be housed at the Manchester Institute for Biotechnology (MIB) and in the Michael Barber Centre for Collaborative Mass Spectrometry. MIB is the home of research groups from both the faculty of science and engineering (FSE) and the faculty of biology, medicine and health (FBMH). The instrument will be accessible by research groups from both FSE and FBMH and by external collaborators from both academia and industry. It will essentially form a basis for an interdisciplinary network of collaborations within the University of Manchester and beyond. We will use this state-of-the-art equipment to underpin investments by MRC and enable working with industrial partners (e.g. OMass Therapeutics, Waters Corp., BioShape Ltd, AstraZeneca, FujiDiosynth). The new instrument will enhance capacity and capability for investigating challenging biological systems within their native cellular environment. It will offer unsurpassed sensitivity, speed of acquisition and resolution circumventing current limitations in the technique. This will enable broader research access and wider application to many biological processes such as membrane transport, drug development and design, catalysis, and large molecular machines and related diseases such as cancer, tuberculosis, heart failure and antimicrobial resistance. This will further offer the ability to carry out research in human samples and in their native environments.