Towards better predictions designs and engineering of coiled-coil protein-protein interactions

生物学已经迅速成为一门分子科学：生物学的蓝图是由分子绘制的，由分子构建并由分子运行；我们现在有了在分子水平上研究和理解生物学的方法。生物分子有各种各样的形状和大小，从直径不到十亿分之一米的水分子，到伸展开来可以跨越几十厘米的DNA分子。较大的分子被称为生物大分子，其中有四种类型：碳水化合物、脂类、核酸和蛋白质。它们中的大多数在生物学中执行由它们的化学性质决定的任务。蛋白质是我们研究的主题，它的不同寻常之处在于，它们在生物学中发挥着各种各样的功能。例如，胶原蛋白在大多数哺乳动物组织中提供支架和加固；肌红蛋白在肌肉中储存氧气，而它的亲戚血红蛋白则将氧气从肺部输送到活跃的器官和组织；而己糖激酶是一系列酶（催化化学反应的蛋白质）中的第一个酶，它能分解含葡萄糖的食物，产生ATP， ATP是生物学中能量的通用货币。上述所有蛋白质的功能都依赖于它们采用特定的三维形状。为了认识和理解这一点，这是我们研究的一个长期目标，需要一些蛋白质化学：首先，蛋白质是聚合物；也就是说，它们是由类似的构建块组成的链状分子，由称为肽键的强链接连接在一起。一般来说，聚合物不采用特定的三维结构。蛋白质的不寻常之处在于，这是它们在生物学中的作用和重要性的关键。蛋白质采用或折叠形成特定结构的原因归结为多肽链和所使用的构建块。蛋白质主要由20个氨基酸组成。氨基酸具有不同的化学性质，例如，一些氨基酸可溶于水，而另一些则不能，最终，这些决定了完整蛋白质的功能。蛋白质的三维结构是由多肽链上氨基酸的排列顺序决定的，这就是蛋白质序列。即使经过了50多年的研究，科学家们仍然不明白蛋白质的结构和功能是如何与其序列相关联的。这个谜题被称为蛋白质折叠问题，也是本次拨款提案的主题。从这个角度来看，对于一个有100个氨基酸的蛋白质，这对蛋白质来说是很小的，有20的100次方个可能的序列。虽然这是生物学的一个伟大资源——它是一个巨大的不同潜在蛋白质的资源库，但对于科学家来说，这是一个非常令人生畏的数字。那么，如果蛋白质折叠问题这么长时间没有得到解决，我们将如何做出贡献呢？我们将重点关注一种蛋白质，其成员具有相似的序列，但却采用各种不同的结构。这些被称为盘绕线圈。它们存在于所有的生物系统中，并执行许多不同的功能，包括帮助打开基因，并在细胞内外提供支架材料。它们主要负责将蛋白质分子聚集在一起，这是生物学中必不可少的过程，因为蛋白质不是单独工作，而是协同工作。我们将收集许多线圈序列和结构的例子，并将它们结合起来。通过比较和对比与不同结构相关的序列，我们的目标是学习将序列与结构联系起来的规则。有了这些规则，我们将能够在新兴的基因组中预测新的卷曲线圈的例子，甚至可能创造出我们自己的卷曲线圈蛋白质，用于医学应用，比如组织工程的支架。

Biology has rapidly become a molecular science: biology is blueprinted by, built from and run by molecules; and we now have the means to examine and understand biology at the molecular level. Biological molecules come in all shapes and sizes, ranging from water molecules that measure less than one billionth of a metre across, to molecules of DNA that, when stretched out, can span tens of centimetres. The larger molecules are called biological macromolecules, of which there are four types: carbohydrates, lipids, nucleic acids and proteins. Most of these perform tasks in biology dictated by their chemistry. Proteins, which are the subject of our research, are unusual in that they perform a wide variety of functions in biology. For example, collagen provides scaffolding and reinforcement in most mammalian tissues; myoglobin stores oxygen in muscle, whereas its relative, haemoglobin, transports oxygen from the lungs to active organs and tissues; and hexokinase is the first in a cascade of enzymes--proteins that catalyse chemical reactions--that breaks down glucose-containing foodstuffs to make ATP, the universal currency of energy in biology. The functions of all of the above proteins depend on them adopting specific three-dimensional shapes. To appreciate and to understand this, which is one long-term objective of our research, some protein chemistry is required: firstly, proteins are polymers; that is, they are chain-like molecules made from similar building blocks held together by strong links called peptide bonds. In general, polymers do not adopt specific three-dimensional structures. Proteins are unusual in that they do, which is the key to their roles and importance in biology. The reason that proteins adopt, or fold up to form specific structures comes down to the polypeptide chain and the building blocks used. Proteins predominantly use a set of just twenty amino-acid building blocks. The amino acids have different chemistries, for instance, some are soluble in water, whereas others are not, and, ultimately, these determine the functions of the intact proteins. The three-dimensional structures of proteins are determined by the order of amino acids along the polypeptide chain, which is known as the protein sequence. Even after more than fifty years of research, scientists do not understand how a protein's structure, and hence its function, is related to its sequence. This riddle is known as the protein-folding problem and is the subject of this grant proposal. To put this into perspective, for a protein of 100 amino acids, which is on the small side for proteins, there are 20 to the power 100 possible sequences. Whilst a great resource for biology--it is a huge pool of different potential proteins to explore--this is a very daunting number for scientists to consider. So if the protein-folding problem has remained unsolved for so long, how will we contribute? We will focus on one type of protein the members of which have similar sequences, but nonetheless adopt a variety of different structures. These are called coiled coils. They occur in all biological systems, and carry out many different functions, including helping to switch genes on, and providing scaffolding material within and outside cells. Predominantly, they are responsible for bringing protein molecules together, which is an essential process in biology as proteins do not work alone but in concert. We will gather together many examples of coiled-coil sequences and structures and marry them up. By comparing and contrasting the sequences associated with the different structures, we aim to learn rules that link sequence to structure. Armed with these rules, we will be able to predict new examples of coiled coils in the emerging genomes, and possibly even create our own coiled-coil proteins for medical applications such as scaffolds for tissue engineering.