Modular protein design for spatial control and organisation

蛋白质在生物系统中发挥着从结构支持到运动、通讯和催化的大部分功能。模块化蛋白质结构被设计成具有特定的几何、空间和构象属性，可以用于解决与从生物复合材料到细胞培养的几个研究领域相关的问题，该项目将致力于探索其中几个的可能性。这些蛋白质的计算蛋白质设计将主要使用Rosetta建模套件(www.rosettalommons.org)和Elfin包(https://github.com/joy13975/elfin)由Parmegiani实验室开发)来完成。这项研究将把蛋白质建模与结构生物学和功能分析相结合，从设计概念到实验验证。最初的工作将集中在根据现有的重复蛋白质单元数据库建立的几个新的模块化蛋白质结构的计算设计和实验验证上。这些设计将朝着两个主要领域发展，作为干细胞培养的配体展示支架和用于生物复合材料应用的伸展蛋白质单元。两个关键的探索领域--伸展结构的设计和这些单元可能的更大组装，以及它们在天然纤维复合材料中作为间隙增强剂的能力，以及在复合材料中的其他几种可能的用途。这项工作将与布里斯托尔大学工程学教授Fabrizio Scarpa教授合作。-设计用于人工干细胞培养环境的配体展示支架。通过这些有组织的配体展示支架控制干细胞培养中受体激活的能力可以改进干细胞培养方法，并降低与配体内化相关的成本。功能分析将与阿什利·托伊博士(布里斯托尔大学生物化学)小组合作进行。这项工作还将包括开发一种计算设计流水线，用于高效生产这些更大的有组织的模块化蛋白质结构，这将被证明是有效设计未来蛋白质的有用工具，用于不同空间组织的应用。

Proteins perform most of the functions in biological systems, from structural support, to movement, communication and catalysis. Modular protein structures designed to have specific geometric, spatial and conformational properties could be applied to solve problems relating to several fields of research, from biocomposites to cell culture, and this project will aim to explore the possibilities of several of these.Computational protein design of these proteins will be done using mainly the Rosetta modelling suite (www.rosettacommons.org) and the Elfin package (https://github.com/joy13975/elfin) developed by the Parmeggiani Lab. This research will combine protein modelling with structural biology and functional assays, going from design concepts to experimental validation.Initially the work will focus on the computational design and experimental validation of several novel modular protein structures built from the existing database of repeat protein units available. These designs will be developed towards two major areas of interest, as ligand display scaffolds for stem cell culture, and as auxetic protein units for use in biocomposite applications.Two key areas of exploration -- Design of auxetic structures and possible larger assemblies of these units, and investigation of their ability as interstitial strengtheners in natural fibre composites, alongside several other possible uses within composite materials. This work will be in collaboration with the group of Prof Fabrizio Scarpa (Engineering, University of Bristol).- Design of ligand display scaffolds for use in artificial stem cell culture environments. The ability to control receptor activation in stem cell culture via these organised ligand display scaffolds could improve stem cell culture methods and reduce costs associated with ligand internalisation. Functional assays will be performed in collaboration with the group of Dr Ashley Toye (Biochemistry, University of Bristol).This work will also incorporate the development of a computational design pipeline for the efficient production of these larger organised modular protein structures, which will prove a useful tool in the efficient design of future proteins for applications with varying spatial organisations.