Macromolecular structure determination using pulsed electron spin resonance techniques.

在生物学中，通常有可能对特定生物分子（如蛋白质）的功能有很好的理解。生物学家还开发了一些工具，使他们能够了解制造这种蛋白质的元素序列，并了解其整体结构（通常是非常详细的）。然而，生物学所不擅长的是将蛋白质的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，以及在相互作用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，因为它通常是药物开发策略的基础。一种很有前途的新兴方法可以解决这个问题，它使用化学来精确地定位微小的磁性分子在每个较大的生物分子中的相同位置。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。在这个提案中，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项目下开发的，我们可以提高这些类型测量的灵敏度和时间分辨率，相对于通常花费在50万英镑到100多万英镑之间的商业仪器，我们可以提高这些测量的数量级。我们认为这一建议具有突出的价值，因为所有高风险技术都已经开发并集成到一个工作系统中。我们也有一个完全发展和雄心勃勃的应用程序，针对生物学中的重要问题，我们有初步的数据，并完全支持商业仪器的可用性。因此，我们相信这是一个相对低风险但高回报的项目，有望为寻求理解结构/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.