A biomolecular-design approach in synthetic biology: towards synthetic cytoskeletons

合成生物学中的生物分子设计方法：合成细胞骨架

• 批准号: BB/G008833/1
• 负责人: Dek Woolfson
• 金额: $ 85.79万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG008833%2F1
• 关键词: biomolecular; design; approach; synthetic; biology

Biology provides a wealth of information, materials and inspiration for engineering new biomaterials and functional systems. In turn, these new entities may find applications in areas from electronics through to medicine. It is early in the development of our understanding of the principles upon which biological components--proteins, cells, tissues etc--are built; and we are only just beginning to tap the potential of this knowledge. Endeavours to reduce biological complexity to principles and manageable building blocks, and then piece these together to form new materials and systems are known as 'synthetic biology'. This is a very new and exciting science. There's a catch, however: we're not very good at it at the moment. Natural biological systems largely comprise six types of molecule: carbohydrates, lipids, nucleic acids, proteins, a wide variety of 'small molecules' and water. Each of these have their own niche functions: water is the solvent; amongst other things, small molecules provide the common currency of energy and rapid means of signalling throughout biology; carbohydrates provide structure and accessible sources of energy; lipids form the membranes that wrap up cells and functional compartments within cells; and nucleic acids store and pass on the information to make proteins, cells and so on. We have left proteins until last as they are somewhat unique in that they perform a myriad of functions: some are structural, others signal, many act on small molecules, more still provide the basis of our defence and immune systems, and so on. A key feature of Nature is that it uses 'self-assembly' to piece its components together--i.e., the above biomolecules are somehow programmed to interact and cooperate in precise ways--which is very different from how our everyday technologies are currently built. This proposal has two broad aims: first, we aim to reduce the complexity of Nature and create a toolkit of bioinspired building blocks, which will allow the programmed and reliable self-assembly of new biomaterials and functional systems. Second, we will make a start at piecing the building blocks together to form biomimetic systems that capture the key features of biological assemblies such as networks of proteins and cells, albeit crudely in the first instance. One of the targets of our study are small proteins called peptides, which can be made in the lab relatively easily. We wish to learn from Nature how the different chemistries of certain peptides instructs them to form the well-defined 3D structures upon which much of biology is built. This will require examining natural peptides, finding 'rules' that drive their folding and self-assembly. Our second targets are the lipid membranes. We need these to help encapsulate the protein assemblies that we plan to make, and we need encapsulation so that we can gain some control over the systems that we aim to generate. This is precisely why biology uses encapsulation. Why do all of this? The famous physicist, Richard Feynman once remarked that what he could not build, he did not understand. This is the principle that we have adopted for our research: we plan to look at natural biological systems, learn from them, and then test our understanding by designing and attempting to construct new simplified systems. This will not be easy and there is a risk of failure. However, the potential rewards are high: we stand to learn how some of biology's components assemble at the very least; and this understanding can then be applied by us and by others to create new biomaterials, devices and systems that might eventually find applications in medicine, electronics and analytical science.

生物学为设计新的生物材料和功能系统提供了丰富的信息，材料和灵感。反过来，这些新实体可能会在从电子到医学的各个领域找到应用。我们对生物成分-蛋白质、细胞、组织等-所依据的原理的理解还处于早期阶段;我们才刚刚开始挖掘这一知识的潜力。努力将生物复杂性简化为原则和可管理的构建模块，然后将这些组合在一起形成新的材料和系统，这被称为“合成生物学”。这是一个非常新的和令人兴奋的科学。然而，有一个问题：我们目前并不擅长。自然生物系统主要包括六种类型的分子：碳水化合物，脂质，核酸，蛋白质，各种各样的“小分子”和水。其中每一种都有自己的生态位功能：水是溶剂;除其他外，小分子在整个生物体中提供能量的共同货币和快速的信号传递手段;碳水化合物提供结构和可获得的能量来源;脂质形成包裹细胞和细胞内功能区室的膜;核酸储存并传递信息以制造蛋白质、细胞等。我们把蛋白质留到最后，因为它们有些独特，因为它们执行无数功能：一些是结构性的，另一些是信号性的，许多作用于小分子，更多的仍然是我们防御和免疫系统的基础，等等。自然界的一个关键特征是它使用"自组装"将其组件拼凑在一起--即，上述生物分子以某种方式编程，以精确的方式相互作用和合作--这与我们目前日常技术的构建方式非常不同。该提案有两个广泛的目标：首先，我们的目标是降低自然的复杂性，并创建一个生物启发的构建模块工具包，这将允许新生物材料和功能系统的程序化和可靠的自组装。其次，我们将开始将构建模块拼凑在一起，形成仿生系统，以捕捉生物组装的关键特征，如蛋白质和细胞的网络，尽管在第一个实例中很粗糙。我们研究的目标之一是称为肽的小蛋白质，它可以在实验室中相对容易地制造。我们希望从大自然中了解某些肽的不同化学性质如何指导它们形成定义明确的3D结构，而生物学正是建立在这些结构上的。这将需要检查天然肽，找到驱动其折叠和自组装的“规则”。我们的第二个目标是脂膜。我们需要这些来帮助封装我们计划制造的蛋白质组装体，我们需要封装，这样我们就可以对我们想要生成的系统进行一些控制。这正是生物学使用封装的原因。为什么要这么做？著名的物理学家理查德·费曼曾经说过，他不能建造的东西，他不理解。这是我们在研究中采用的原则：我们计划观察自然生物系统，从中学习，然后通过设计和尝试构建新的简化系统来测试我们的理解。这并不容易，而且有失败的风险。然而，潜在的回报是很高的：我们至少可以了解生物学的一些组件是如何组装的;然后我们和其他人可以应用这种理解来创造新的生物材料，设备和系统，最终可能会在医学，电子学和分析科学中找到应用。

项目成果

The d'--d--d' vertical triad is less discriminating than the a'--a--a' vertical triad in the antiparallel coiled-coil dimer motif.

d--d--d 垂直三联体比反平行卷曲螺旋二聚体基序中的 a--a--a 垂直三联体具有更少的辨别力。

• DOI: 10.1021/ja208855x
• 发表时间: 2012
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Steinkruger,JayD;Bartlett,GailJ;Hadley,ErikB;Fay,Lindsay;Woolfson,DerekN;Gellman,SamuelH
• 通讯作者: Gellman,SamuelH

Self-assembling cages from coiled-coil peptide modules.

从盘绕螺旋肽模块的自组装笼子。

• DOI: 10.1126/science.1233936
• 发表时间: 2013-05-03
• 期刊: Science (New York, N.Y.)
• 作者: Fletcher JM;Harniman RL;Barnes FR;Boyle AL;Collins A;Mantell J;Sharp TH;Antognozzi M;Booth PJ;Linden N;Miles MJ;Sessions RB;Verkade P;Woolfson DN
• 通讯作者: Woolfson DN

A de novo peptide hexamer with a mutable channel.

• DOI: 10.1038/nchembio.692
• 发表时间: 2011-10-30
• 期刊: NATURE CHEMICAL BIOLOGY
• 影响因子: 14.8
• 作者: Zaccai, Nathan R.;Chi, Bertie;Thomson, Andrew R.;Boyle, Aimee L.;Bartlett, Gail J.;Bruning, Marc;Linden, Noah;Sessions, Richard B.;Booth, Paula J.;Brady, R. Leo;Woolfson, Derek N.
• 通讯作者: Woolfson, Derek N.

Membrane proteins by accident or design.

膜蛋白是偶然或设计的。

• DOI: 10.1016/j.cbpa.2013.10.005
• 发表时间: 2013
• 期刊: Current opinion in chemical biology
• 影响因子: 7.8
• 作者: Simms J