Decorating self-assembled nano-to-mesoscale peptide fibres with functional proteins and protein complexes

我们的研究关注的是了解生物学如何使用分子构建块来构建功能结构。我们将这一理解应用于使从分子中获得的新结构在实验室中可用。特别是，我们对制造十亿分之一到百万分之一米的纤维结构感兴趣。有了这样的“纳米纤维”，我们希望用其他“功能”生物分子来装饰它们。通过这种方式，我们的目标是利用自组装过程，自下而上地建立复杂的分子排列。我们的灵感来自生物学，它使用类似的原理来制造具有各种功能的结构；例如，赋予细胞形状和稳定性；在细胞内提供分子高速公路；以及充当将细胞连接在一起并形成组织的脚手架。我们旨在制造的结构可能在新兴的生物纳米技术领域具有长期用途。例如，作为实验室中生长细胞甚至新组织的人造支架，这反过来可能对器官替换的伤口愈合有用。生物学是一门分子科学：它由分子绘制蓝图，由分子构建和运行；我们现在有了在分子水平上检查和理解生物学的手段。生物分子的范围从直径不到十亿分之一米的水分子，到当拉伸时可以跨越数十厘米的DNA分子。较大的分子被称为大分子，包括碳水化合物、脂肪、核酸和蛋白质。它们中的大多数执行由它们的化学物质决定的生物学任务。蛋白质是我们研究的对象，它的不同寻常之处在于它们具有广泛的功能。例如，胶原蛋白在大多数哺乳动物组织中提供支架；肌红蛋白在肌肉中储存氧气，而它的近亲血红蛋白将氧气从肺部输送到活跃的器官和组织；己糖激酶是一系列酶中的第一种，这些酶分解含葡萄糖的食物，制造ATP，这是生物中的能量货币。蛋白质是聚合物：它们是由相似的氨基酸组成的链状分子，通过强键连接在一起。一般来说，聚合物不采用特定的3D结构。蛋白质的不同寻常之处在于它们确实存在，这是它们在生物学中的作用和重要性的关键。蛋白质中的氨基酸有不同的化学成分，例如，有些可以溶于水，有些则不能。最终，这些性质决定了蛋白质的3D结构和功能，但具体是如何决定的还不清楚。蛋白质分子的组织并不仅限于此：它们很少单独行动，更多的时候是组装成更大、更复杂的结构。正是这些复合体通常具有有趣的生物功能。例如，肌红蛋白只有一条蛋白链，其功能有限。然而，血红蛋白中四条链之间的化学相互作用使其具有实用价值：血红蛋白拾取、运输和输送氧气；此外，它完成这一任务的能力可以调整，例如允许胎儿抢走母亲的氧气。我们感兴趣的是一种蛋白质，它能引导和粘合蛋白质链之间的相互作用。这被称为盘绕线圈。在其他方面，它负责制造像豪猪刺这样的结构。我们的利益下降了几个数量级，从十亿分之一米到百万分之一米的规模。我们已经在实验室里成功地制造了纤维结构，就像羽毛一样，达到了这种规模。我们的下一步是用其他功能蛋白质来装饰它们，包括可以传递电子来制造纳米线的蛋白质；制造新抗生素的酶复合体；以及帮助培养神经细胞的细胞生长因子，用于基础科学甚至外科手术。这项提议的目的是创造必要的方法和工具，将裸露的纤维与活性蛋白质联系起来。

Our research is concerned with understanding how biology builds functional structures using molecular building blocks. We apply this understanding to make new structures from molecules accessible in the lab. In particular, we are interested in making fibrous structures at the scale of billionths to millionths of a metre. With such 'nanofibres' in hand, we wish to decorate them with other 'functional' biological molecules. In this way, we aim to build up complex arrangements of molecules from the bottom-up, using the process of self-assembly. Our inspiration comes from biology, which uses similar principles to make structures with a wide variety of functions; for instance, to give shape and stability to cells; to provide molecular highways within cells; and to act as scaffolds that hold cells together and form tissues. The structures that we aim to make may have long-term uses in the emerging area of bionanotechnology. For instance, as man-made scaffolds for growing cells and even new tissues in the lab, which in turn may be useful in wound healing for organ replacements. Biology is a molecular science: it 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 range 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 macromolecules, and include 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 have a wide variety of functions. For example, collagen provides scaffolding 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 that breaks down glucose-containing foodstuffs to make ATP, the currency of energy in biology. Proteins are polymers: they are chain-like molecules made from similar amino-acid building blocks held together by strong bonds. In general, polymers do not adopt specific 3D structures. Proteins are unusual in that they do, which is the key to their roles and importance in biology. The amino acids in proteins have different chemistries, for instance, some are soluble in water, and others are not. Ultimately these properties determine the 3D structures and functions of proteins, but precisely how is not understood. The organisation of protein molecules does not stop there: they rarely act alone and more often assemble into larger more-complex structures. It is these complexes that usually have the interesting biological functions. For instance, myoglobin has only one protein chain, and its function is limited. Whereas, chemical interplay between the four chains in haemoglobin gives it utility: haemoglobin picks up, transports and delivers oxygen; moreover, its abilities to do this can be tuned, for instance to allow a foetus to rob its mother of oxygen. We are interested in one type of protein that directs and cements interactions between protein chains. This is called the coiled coil. Amongst other things, it is responsible for making structures like porcupine quills. Our interests are down a few orders of magnitude at the scale of billionths to millionths of a metre. We have succeeded in making fibrous structures, like the quills, in the lab on this scale. Our next step is to decorate them with other functional proteins, including proteins that can transfer electrons to make nanowires; complexes of enzymes to make new antibiotics; and cell growth factors to help grow nerve cells for fundamental science and perhaps even surgery. The aim of this proposal is create the necessary methods and tools for linking the bare fibres to the active proteins.