Single alpha helical domains: designing artificial levers for biological molecules

DNA编码蛋白质序列，蛋白质序列由折叠成精确三维结构的氨基酸链组成。蛋白质是生命所必需的，不同蛋白质的结构决定了它们在细胞中的工作方式，例如作为酶或结构蛋白。因此，发现控制蛋白质如何折叠成三维结构的原理是理解生命的关键，了解疾病中出了什么问题，以及设计具有有用特性的新蛋白质，例如，使我们能够将人造药物靶向疾病靶点，如癌细胞。折叠蛋白质包含一系列明确的结构构建块。其中之一是阿尔法螺旋，它看起来有点像螺旋弹簧。为了理解蛋白质如何折叠成它们的三维结构，α-螺旋的性质已经被深入研究。在大多数情况下，α-螺旋本身在水中并不非常稳定：它们折叠成随机折叠的链。然而，我们最近发现，有一种天然存在的α螺旋在水中非常稳定。这种稳定的α螺旋存在于从细菌到人类的各种蛋白质中，包括对细胞运动和细胞分裂重要的蛋白质。目前，我们对是什么使它如此稳定，或者它在蛋白质中的功能知之甚少。它通常夹在蛋白质的两个区域之间，我们认为它们可能在蛋白质的两个部分之间充当刚性连接器（或支柱），并将蛋白质一部分的结构变化信息传递到另一部分。我们想找出是什么让这些α螺旋如此稳定，并通过确定人工和天然存在的α螺旋的机械特性来测试我们关于它们的想法，我们认为这些α螺旋在水中形成稳定的α螺旋。为了在短时间内了解尽可能多的信息，我们希望有两个具有不同技能的研究人员一起研究这些螺旋，一次一个分子。他们中的一个将设计一系列含有这些α螺旋的蛋白质，并确定它们的功能如何取决于氨基酸的序列。另一位研究人员将使用一种新的仪器来找出这些工程蛋白质的机械特性，这种仪器可以让我们研究单个分子在拉伸时如何展开，在释放时如何重新折叠，并且还将在计算机中创建模型来解释结果并预测新的特性。他们还将这些蛋白质发送给我们在美国的合作者，他们可以使用自己的专业方法发现它们的其他特性。通过使用尽可能广泛的技术来研究这种稳定的α螺旋，我们认为我们将确定它为何如此稳定，以及哪些蛋白质需要它。

DNA encodes the sequences of proteins, which consist of chains of amino acids that fold up into a precise 3 dimensional structure. Proteins are essential for life, and the structures of different proteins specify how they work in cells, for example as an enzyme or as a structural protein. Discovering the principles that govern how proteins fold up into their three dimensional structure, is therefore key to understanding life, in understanding what goes wrong in disease, and in designing new proteins with useful properties that would, for instance, enable us to target man-made drugs to disease targets such as cancerous cells. Folded proteins contain a series of well-defined structural building blocks. One of these is the alpha helix, which looks a little like a coiled spring. To understand how proteins fold up into their three dimensional structure, the properties of alpha-helices have been intensively studied. In most cases, alpha-helices are not very stable by themselves in water: they collapse into a randomly folded chain. However, we have recently found that there is one type of naturally occurring alpha helix that is remarkably stable all on its own in water. This stable alpha helix is found in a wide variety of proteins from bacteria to humans, including in proteins important for cell movement and cell division. At the moment, we know very little about what makes it so stable, or what its function in protein is. It is usually found sandwiched between two regions of the protein in such a way that we think they might act as stiff linkers (or struts) between the two parts of the protein, and transmit information about changes in structure in one part of the protein to the other part. We want find out what makes these alpha helices so stable, and to test our ideas about what they do, by determining the mechanical properties of artificial and naturally occurring alpha-helices that we think form stable alpha helices in water. To learn as much as possible in a short time, we want to have two researchers with different skills working together to study these helices one molecule at a time. One of them will engineer a series of proteins containing these alpha helices and determine how their function depends on the sequence of the amino acids. The other researcher will find out the mechanical properties of each of these engineered proteins using a new apparatus that lets us study how a single molecule unfolds when it is stretched and refolds when it is released, and will also create models in the computer to explain the results and predict new properties. They will also send these proteins to our collaborators in the USA who can discover additional properties of them using their own specialized methods. By using as wide a range of techniques as possible, to study this stable alpha helix, we think we will determine why it is so stable, and what proteins need it for.