Further development of the PSIPRED server into an integrated tool for systems biology and functional genomics researchers

经过多年的努力，人类基因组初稿于2001年完成，这被誉为一项重大突破，最终将使世界各地的研究人员能够回答与支配复杂生物过程的机制有关的耐人寻味和难以捉摸的问题。现在，人类的基因组可以在几周内完成测序，我们很快就会拥有数千种不同生物的完整基因组。人们希望，从全球基因组数据爆炸中产生的信息将被利用来加深我们的理解，并通过计算机辅助生物学研究应用于有益和治疗用途。大多数基因都被设计成编码特定的蛋白质，这些蛋白质在人体内具有有用的功能。蛋白质本质上是一串更简单的分子，称为氨基酸，一旦蛋白质由细胞中的蛋白质制造机制(核糖体)形成，这些分子串就可以自我组装成复杂的三维结构。正是这种独特的结构决定了蛋白质的确切化学功能(即它在细胞中做什么以及它是如何做的)。通过向结晶蛋白质发射X射线，科学家可以确定它们的结构，但这个过程可能需要数月甚至数年的时间。由于有数十万种蛋白质的天然结构尚不清楚，科学家们想要找到一种聪明的捷径来研究蛋白质的结构也就不足为奇了。像许多其他科学家一样，我们一直在努力破解蛋白质结构的密码，即制定出支配蛋白质如何找到其独特结构的规则，然后试图用这些规则对计算机进行编程，使科学家能够快速地“预测”他们感兴趣的蛋白质的结构。PSIPRED服务是在伦敦大学学院维护的Web服务器的集合，它就是这样做的--它允许生物学家根据氨基酸序列预测蛋白质结构。多年来，它通过提供这些服务帮助了数千名科学家的工作，我们现在不仅希望升级和维护这些现有的服务器，而且还希望实施新的方法，使即使是最困难的蛋白质的结构也可以通过计算机模拟来推断。例如，最近，我们一直在最初的PSIPRED服务的基础上构建，以涵盖生物学中的其他重要问题。这些问题中最大的可能是对已测序基因的生物学功能的预测。在过去的30年里，蛋白质结构和功能之间的关系已经得到了很好的证明，然而自然呈现的多样性和复杂性提出了几个具有挑战性的问题。来自不同物种的基因产物可能表现出匹配的生物学功能，但可能由于趋同进化而显示出很少的或没有序列相似性。这可能是因为，尽管两个蛋白质之间的总体结构和序列相似性很小，但活性部位的关键性质(例如总电荷或近似形状)是保守的，从而允许执行类似的功能。大规模分析蛋白质结构中的功能区不仅可以开发更可靠的基因组注释工具，还可以在细胞水平上增强蛋白质生物学作用的知识库。这种理解将是开发针对病态基因及其产物以及病态生物体蛋白质的技术和药物的关键踏脚石。

The completion of the first draft of the human genome in 2001, after years of effort, was heralded as a major breakthrough that would finally enable researchers throughout the world to answer intriguing and elusive questions relating to the mechanism that govern complex biological processes. Now the genome of a human can be sequenced in a matter of weeks and we will soon have the complete genomes of many thousands of different organisms. The hope is that the information generated from this explosion of genome data worldwide will be harnessed to further our understanding and applied to beneficial and therapeutic use through computer aided biological research. Most genes are designed to code for specific proteins which have useful functions in the body. Proteins are essentially strings of simpler molecules, called amino acids and these strings can self-assemble into a complex 3-D structure as soon as the protein is formed by the protein-making machinery (ribosomes) in the cell. It is this unique structure which determines the precise chemical function of the protein (i.e. what is does in the cell and how it does it). By firing X-rays at crystallised proteins, scientists can determine their structure, but this process can take many months or even years. With hundreds of thousands of proteins for which the native structure is unknown, it is not surprising that scientists want to find a clever shortcut to working out the structure of proteins. We, like many other scientists have been trying to 'crack the code' of protein structure i.e. working out the rules which govern how the protein finds its unique structure and then trying to program a computer with these rules to allow scientists to quickly 'predict' what the structure of their protein of interest might be. The PSIPRED service is a collection of Web servers maintained at UCL which does just this - it allows biologists to predict protein structure from amino acid sequence. Over the years it has helped many thousands of scientists with their work by providing these services and we now wish not only to upgrade and maintain these existing servers but also to implement new methods which allow the structures of even the most difficult proteins to be deduced by computer simulations. More recently, for example, we have been building upon the original PSIPRED service to cover other important problems in biology. Probably the biggest of these problems is the prediction of biological function of sequenced genes. Relationships between protein structure and function have been well documented over the last 30 years, however the diversity and complexity presented by nature poses several challenging problems. Gene products from different species may exhibit the matching biological functions, but may show little or no sequence similarity, perhaps due to convergent evolution. It may be that although there is little overall structural and sequence similarity between two proteins that key properties of the active sites (e.g. overall charge or approximate shape) are conserved allowing similar functions to be carried out. Analyses of functional regions within protein structures on a large scale will not only allow the development of more reliable genome annotation tools but also enhance the knowledge base of the biological role of proteins at a cellular level. Such understanding will be a key stepping stone in the development of techniques and pharmaceuticals to target diseased genes and their products as well as proteins from pathological organisms.