High Precision Charge and Size Spectrometry on Biomolecules and Molecular Complexes in Solution

溶液中生物分子和分子复合物的高精度电荷和尺寸光谱测定

• 批准号: BB/W017415/1
• 负责人: Madhavi Krishnan
• 金额: $ 90.13万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW017415%2F1
• 关键词: Precision; Charge; Size; Spectrometry; Biomolecules

The history of Science is inextricably linked to the history of measurement. As immortalised in the words of the 19th century Dutch Nobel Laureate Kamerlingh-Onnes, discoverer of superconductivity: "Through measurement to knowledge". In scarcely any field of research have these words rung more true than in the biophysical sciences of the last few decades, where the development and refinement of technologies to measure the properties of the molecular building blocks of nature have brought a wave of unprecedented knowledge and insight into the structure and mechanisms underpinning life. The suite of molecular building blocks that make up life is vast, and no single approach offers the answers to the myriad questions scientists may wish to ask. Any new technique that takes a different physical approach can shed new light on a problem, revealing important aspects of it that until then remained entirely out of view. This process of endless improvement and enhancement of measurement techniques plays a defining role in scientific development and underpins the continuous creation of new knowledge. Size, or mass, and electrical charge are two fundamental physical properties that characterise biological molecules. While molecular mass has long been measured with atom-level precision, my laboratory recently developed a new experimental approach to measure the electrical charge of biological molecules with a precision better than a single elementary charge. Since techniques capable of delivering such measurements have been hitherto unavailable, we anticipate being able to add an important new dimension to the existing body of information on biomolecules. An important aspect of our new approach is that unlike most other measurement techniques we are able to access the properties of individual molecules in solution, and are not limited to observing an average value resulting from the sum of all responses of a multitude of molecules in sample. The reason why this matters is that contrary to common sense, a biological molecule of a certain kind is not necessarily identical to all its neighbours. In fact a given molecular species can exist in slightly different states for a number of different reasons. This multitude of states often carries an important signature of the biological function of the species, and such signatures are revealed in "single molecule" measurements performed in a highly parallel fashion. The ability to perform these sorts of measurements in a rapid and highly accurate fashion is still in its infancy.The technology we shall develop aims to offer scientists in the biological, biophysical and biomedical sciences a measurement tool that will offer unprecedented insight into properties of biomolecules such as proteins in solution. Beyond the research laboratory, many medical diagnostic tests rely crucially on the ability to sensitively and reliably detect the presence of particular proteins, either free or bound to specific molecular partners in a patient-derived sample. For example in infectious diseases, a test for whether a patient has had exposure to a pathogen or not relies on detecting molecules called "antibodies" circulating in the bloodstream. This is done by checking whether the antibodies in the patient's serum bind in a reaction tube to antigens used as 'molecular bait'. The availability of a measurement tool to deliver high precision measurements of size and electrical charge on molecular scale matter in a sample will not only revolutionise biological research, but will also put detection tools offering unprecedented sensitivity into the hands of medical testing laboratories continuously on the look-out for faster, cheaper and more accurate diagnostic technologies. Viewed through the lens of societal needs during an outbreak of an infectious disease for example, the importance of new technologies that defend the stability of social structures and economies, upholding the social contract, cannot be overstated.

科学的历史与测量的历史密不可分。正如19世纪世纪荷兰诺贝尔奖获得者、超导发现者Kamerlingh-Onnes所说的那样：“通过测量获得知识”。在过去的几十年里，几乎没有任何研究领域比生物物理科学更能体现这句话的真实性，在生物物理科学中，测量自然界分子构建块属性的技术的发展和完善带来了一波前所未有的知识和洞察力，以了解生命的结构和机制。构成生命的分子构件是巨大的，没有一种方法可以回答科学家可能想问的无数问题。任何采用不同物理方法的新技术都可以为问题提供新的见解，揭示它的重要方面，直到那时仍然完全看不到。测量技术的不断改进和提高在科学发展中起着决定性的作用，并支撑着新知识的不断创造。大小或质量和电荷是表征生物分子的两个基本物理性质。虽然分子质量长期以来一直以原子级的精度测量，但我的实验室最近开发了一种新的实验方法来测量生物分子的电荷，其精度优于单个基本电荷。由于迄今为止还没有能够提供这种测量的技术，我们预计能够为现有的生物分子信息体增加一个重要的新维度。我们的新方法的一个重要方面是，与大多数其他测量技术不同，我们能够访问溶液中单个分子的特性，并且不限于观察样品中大量分子的所有响应之和产生的平均值。这一点之所以重要，是因为与常识相反，某种生物分子不一定与其所有邻居都相同。事实上，一个给定的分子种类可以存在于稍微不同的状态，有许多不同的原因。这种众多的状态通常携带着物种生物功能的重要特征，并且这种特征在以高度并行的方式进行的“单分子”测量中被揭示。快速、高精度地进行这类测量的能力仍处于起步阶段。我们将开发的技术旨在为生物、生物物理和生物医学科学领域的科学家提供一种测量工具，以前所未有的方式深入了解溶液中蛋白质等生物分子的特性。在研究实验室之外，许多医学诊断测试关键依赖于灵敏可靠地检测特定蛋白质的存在的能力，无论是游离的还是与患者来源的样品中的特定分子伴侣结合的。例如，在传染病中，检测患者是否接触过病原体依赖于检测血液中循环的称为“抗体”的分子。这是通过检查患者血清中的抗体是否在反应管中与用作“分子诱饵”的抗原结合来完成的。测量工具的可用性，以提供高精度测量样品中分子尺度物质的大小和电荷，不仅将彻底改变生物研究，而且还将使检测工具提供前所未有的灵敏度，不断寻找更快，更便宜和更准确的诊断技术。例如，从传染病爆发期间社会需求的透镜来看，新技术对于维护社会结构和经济的稳定、维护社会契约的重要性怎么强调都不过分。