CCP4: Low resolution complexes; handling difficult data; empowering structural biologists and supporting UK structural biology

结构生物学是分析生物分子的有力工具。本质上，它定位组成蛋白质和其他生物分子的原子。它在基础科学中用于定义核糖体、离子通道和复杂蛋白质组合(如ATPase)等分子的3D结构。一旦生物模型中所有原子的3D模型可用，就有可能对分子在生物体内的功能做出推断。这种知识在控制这一功能方面有相应的应用，通常导致药物设计方面的医学进步，更好地了解自然环境中的生物和反馈系统，化学工程中的新方法，以及许多其他好处。“解决”结构的过程包括首先获得晶体，然后将它们暴露在X射线下：这相当于使用一个非常强大的显微镜，使我们能够“看到”单个原子。获得晶体本身是非常苛刻的，需要大量的技能和科学洞察力。使用X射线还有一个问题，那就是显微镜没有透镜系统。这意味着记录晶体的间接、所谓的衍射图像。从这些图像中提取数据并进行最终结构的过程是计算密集型的，需要一套与生物学家完全不同的技能。开发新的计算机方法，并将它们关键地嵌入到健壮、易于使用的软件中，将把结构生物学从劳动密集型、高度技术性的过程转变为生物学中的常规工具。这项资助的主要重点是解决3D结构的计算过程。CCP4是一个为该过程的多个阶段收集、开发、打包和分发软件的项目，25年来一直是方法开发的重点，并向在该领域工作的学术和工业团队提供软件。它是将基础科学技术转移到英国一个主要行业--制药开发--的一个很好的例子。这个问题还不能说完全解决了。生物学家首先正在研究越来越困难的结构，这需要新的技术。此外，他们正在解决大量有时相关的结构，例如一系列突变体和复合体，其中自动化的高通量至关重要，系统的记录保存是必不可少的。这项提议的重点是使这些发展成为可能。

Structural Biology is a powerful tool for analysing biological molecules. In essence it locates the atoms that make up proteins and other biomolecules. It is used in basic science to define the 3D structures of such molecules as the ribosome, ion channels and complex protein assemblies such as ATPase. Once a 3D 'model' of all the atoms in the biological model is available, it is possible to make deductions about how the molecule functions within the organism. This knowledge has corresponding applications in controlling that function, often leading to medical advances in drug design, better understanding of biological and feedback systems in the natural environment, new approaches in chemical engineering, and many other benefits. The process of 'solving' the structure involves first obtaining crystals and then exposing these to X-rays: this is equivalent to using a very powerful microscope and allows us to 'see' individual atoms. Getting crystals is in itself very demanding and involves a lot of skill and scientific insight. There is an additional problem in using X-rays in that there is no lens system for the microscope. This means that indirect, so-called diffraction images of the crystal are recorded. The process of extracting data from these images and proceeding to a final structure is computationally intensive and requires an entirely different set of skills from those of the biologist. Developing new computer methods and crucially embedding them in robust easy-to-use software will transform structural biology from a labour intensive highly technical process to a routine tool in biology. The main focus of this grant is on the computational process of solving 3D structures. CCP4 is a project which has collected, developed, packaged and distributed software for the many stages of this process, acting as a focus for methods development for over 25 years and making software available to both Academic and Industrial teams working in this area. It is an excellent example of technology transfer of basic science into a major UK Industry: Pharmaceutical development. The problem cannot yet be said to be totally solved. Biologists firstly are tackling more and more difficult structures, which require novel techniques. In addition, they are solving large number of sometimes related structures, such as a series of mutants and complexes, where automated high throughput is vital and systematic record keeping is essential. This proposal is focussed on enabling these developments.