Exploiting Engineered Polyproteins in the Modular Design of Robust, Tuneable and Biofunctional Hydrogels

蛋白质是生物机器。这些细胞的主力负责大量的生物功能。它们单独行动或作为更大、通常更复杂的机械的一部分，通过结构和机械变化来执行其功能。对自然界中蛋白质力学性能的研究为设计具有先进力学性能平衡的新材料提供了许多灵感。这包括巨大肌肉蛋白titin的高机械强度，断裂韧性和弹性以及天然丝纤维的迷人机械性能的显着组合。尽管自然界具有明显的生物复杂性，但研究表明，蛋白质可以被设计成成功地模仿肌肉的力量和被动弹性。这是通过设计多聚蛋白实现的，多聚蛋白含有特定数量和排列的蛋白质结构域。多聚蛋白是重要的，因为它们在实验中提供了清晰的机械指纹，用于监测蛋白质对施加的机械力的响应。多聚蛋白可以使用聚合物物理学来描述，并且可以使用诸如单分子力光谱（SMFS）的工具来操纵，该工具提供关于其机械稳定性和柔软性的信息。多聚蛋白中存在的等级结构和分子间相互作用以及它们形成的网络提供了新的机会。特别是，最近令人兴奋的发展是使用多聚蛋白作为水凝胶中的结构单元。水凝胶是三维的、水合的、高度多孔的、跨越宏观尺寸的聚合物网络。水凝胶领域现在很广泛，在英国具有相当大的优势。然而，直到最近，由于称为重组DNA技术的生物技术的进步，才可以探索基于多蛋白的水凝胶。由工程化多蛋白组成的水凝胶提供三个关键优点：（i）多蛋白链的模块化设计可以用于模拟自然界中发现的有吸引力的机械和结构层次，（ii）折叠的球状蛋白质提供了具有序列依赖性和可调节的热力学和机械性质的结构单元，（iii）功能性是蛋白质折叠所固有的，允许结合响应生物分子提示的特异性生物识别能力。因此，基于多聚蛋白的水凝胶是软物质和生物物理学中令人兴奋的新兴领域。折叠蛋白质的整体功能为组织工程和干细胞分化等应用提供了巨大的机会，并为微光学，生物传感器和药物控释提供了智能，响应性材料的途径。虽然存在用于测量蛋白质和水凝胶的结构、动力学和力学的工具，但关于这些信息如何在纳米尺度和介观尺度之间转换的知之甚少。水凝胶设计的系统和合理的方法需要系统的机械和结构特性在层次组织的所有水平上被理解。该奖学金将提供一个平台，用于生产具有特定生物功能的多蛋白水凝胶，从而响应生物分子线索，实现机械和结构特性的动态变化。所采用的实验和理论方法将为软物质物理学和生物物理学的探索提供丰富的领域，定义水凝胶领域令人兴奋的新方向，并导致发现新的生物材料。

Proteins are bionanomachines. These workhorses of the cell are responsible for a vast array of biological functions. Acting in isolation or as part of larger, often complex machinery, they perform their function through structural and mechanical changes. Studies on the mechanical properties of proteins found in nature have provided much inspiration for the design of new materials that have a balance of advanced mechanical properties. This includes the remarkable combination of high mechanical strength, fracture toughness and elasticity in the giant muscle protein titin and the intriguing mechanical properties of natural silk fibres. Despite the apparent biological complexity of nature, studies have shown that proteins can be designed to successfully mimic the strength and passive elasticity of muscle. This has been achieved through the design of polyproteins, which contain a specific number and arrangement of protein domains. Polyproteins are important because they provide a clear mechanical fingerprint in experiments for monitoring the response of proteins to an applied mechanical force. Polyproteins can be described using polymer physics and can be manipulated using tools such as single molecule force spectroscopy (SMFS), which provides information on their mechanical stability and softness. The hierarchical structures and intermolecular interactions present in polyproteins and the networks they form present new opportunities. In particular, a recent exciting development is the use of polyproteins as building blocks in hydrogels. Hydrogels are three-dimensional, hydrated, highly porous, percolating polymer networks spanning macroscopic dimensions. The hydrogel field is now extensive, with considerable strengths in the UK. However, it is only very recently that polyprotein-based hydrogels can be explored, due to advances in a biological technique called recombinant DNA technology.Hydrogels composed of engineered polyproteins offer three key advantages (i) the modular design of the polyprotein chain can be used to mimic the attractive mechanical and structural hierarchy found in nature, (ii) folded globular proteins offer building blocks with sequence dependent and tuneable thermodynamic and mechanical properties, (iii) functionality is intrinsic to protein fold, allowing for the incorporation of specific biological recognition capabilities that respond to biomolecular cues. Polyprotein-based hydrogels are therefore an exciting, emerging area in soft matter and biophysics. The integral functionality of the folded protein offers huge opportunities for applications, such as tissue engineering and stem cell differentiation, as well as offering a route towards smart, responsive materials for micro-optics, biosensors, and controlled release for drugs. While tools exist for measuring the structure, dynamics and mechanics of both proteins and of hydrogels, little is known about how this information translates between the nano- and mesoscopic length scales. A systematic and rational approach to hydrogel design requires the mechanical and structural properties of the system to be understood at all levels of hierarchical organisation. This fellowship will deliver a platform for the production of polyprotein hydrogels that possess specific biological function capabilities, enabling dynamic changes in mechanical and structural properties in response to biomolecular cues. The experimental and theoretical methods employed will provide a rich area for exploration in soft matter physics and biophysics, define exciting new directions in the hydrogel field, and lead to the discovery of novel biomaterials for exploitation.