Macromolecular structure determination using pulsed electron spin resonance techniques.

在生物学中，通常可以很好地理解特定生物分子（如蛋白质）的功能。生物学家还开发了一些工具，这些工具通常使他们能够理解制造蛋白质的元素序列，并了解其整体结构/通常是精致的细节。然而，生物学不太擅长的是将蛋白质结构与其功能联系起来。它缺乏精确的工具来理解蛋白质或其他生物分子如何相互作用，以及在这种相互作用过程中发生了什么微观变化。然而，对这种结构/功能关系的详细了解是至关重要的，因为它往往是药物开发策略的基础。解决这个问题的一种有前途的新兴方法使用化学方法将微小的磁性分子准确地定位在每个较大生物分子内的完全相同的位置。然后使用先进的磁共振技术来获得有关这些探针周围的局部结构和动力学的定量信息，并使用它们来了解蛋白质，RNA或DNA之间的相互作用。在本提案中，我们希望证明，使用新技术，最近在一个主要的顶级英国基础技术计划下开发的，我们可以提高这些类型的测量的灵敏度和时间分辨率的数量级相对于商业仪器通常花费£ 0.5米到超过£ 1米。我们相信，这一建议是突出的价值，因为所有的高风险技术已经开发和集成到一个工作系统。我们还有一个针对生物学中重要问题的全面开发和雄心勃勃的应用程序，我们有初步数据，并且完全得到商业仪器的支持。因此，我们相信这是一个相对低风险但高回报的项目，有望为寻求了解结构/功能问题的生物学家提供新的有效工具。

In biology it is often possible to have a good understanding of the function of a particular biomolecule such as a protein. Biologists have also developed tools that often allow them to understand the sequence of elements that make that protein and understand its overall structure / often in exquisite detail. However, what biology is considerably less good at is relating that proteins structure to its function. It lacks precise tools to understand how proteins or other biomolecules interact with one another and what microscopic changes occur during that interaction. Yet a detailed understanding of this structure/function relationship is vital as it often underpins drug development strategies. One promising emerging methodology to solve that problem uses chemistry to accurately locate tiny magnetic molecules in exactly the same position within each larger biomolecule. Advanced magnetic resonance techniques are then used to derive quantitative information about the local structure and dynamics around those probes as well as using them to understand interactions between proteins, RNA or DNA. In this proposal we wish to demonstrate that using new technologies, recently developed under a major top-rated UK Basic Technology program, we can improve sensitivity and time resolution of these type of measurements by orders of magnitude relative to commercial instrumentation typically costing between £0.5M to more than £1M. We believe that this proposal is outstanding value as all the high risk technologies have already been developed and integrated into a working system. We also have a fully developed and ambitious applications program targeting important problems in biology, where we have preliminary data and where it is completely underpinned by the availability of commercial instrumentation. We thus believe this is a relatively low risk but high reward project that promises provide new and effective tools for biologists seeking to understand structure/function problems.