Supramolecular Systems Capable of Bio-inspired Communication and Recognition

超分子化学的灵感往往来自于自然界的功能性和复杂性。虽然在实现生物分子机器的人工模拟方面取得了长足的进步，但合成系统一直无法与生物学协同过程至关重要的特异性和方向性相匹配。在这里，我将开发新的工具来赋予人工超分子系统与其生物同行所见的功能。在最初的四年里，我将创建具有前所未有的靶标结合特异性的体系结构，以及能够跨生物相关膜传输信息的系统。在接下来的三年里，我将合作将这些应用于生物领域，旨在通过创造从头开始的催化酶类似物，使合成细胞受体的设计成为可能，并产生靶向药物输送载体，从而对生物医学和合成生物学产生长期影响。从长远来看，这一提议将提供修复并最终替换有缺陷的生物系统的新方法，从而治疗难治性疾病。生物系统的复杂性和功能性源于生物分子的信息丰富性，以及它们的可控分布和运动。这些特性允许完成要求苛刻的任务；生物机器，如三磷酸腺苷合成酶，跨膜协同工作，维持动态平衡，信息丰富的酶通过靶向相互作用转换特定的分子。相比之下，当前一代的超分子组装缺乏自然界中存在的靶向识别，并且通常无法协同工作，因为它们的运动不能定向。这项研究提案将提供工具来弥合这一差距，解决超分子化学中尚未满足的挑战。我将开发定位于膜上的联锁结构，作为跨膜受体的新型类似物，如GPCRs，以及具有靶向功能的信息丰富的分子胶囊，能够模仿酶的结合特异性和催化功能。我的建议首先，开发可以嵌入膜的联锁结构(结合我在人工分子机器和轮烷形成方面的专业知识，以及King‘s和Crick的膜科学专业知识)，并将信息从隔室外传输到内部。这将通过物理地耦合两个隔室来实现内部环境的调制，而不需要信号分子通过膜。因此，我将创造新的跨膜信号蛋白类似物。我们将利用这项技术来创造细胞受体的人工类似物，在合成生物学和治疗囊性纤维化和德拉韦综合征等渠道疾病方面具有潜在的应用。其次，这项提议将把生物系统的信息密度与金属-有机胶囊的明确空腔结合起来，利用我在自组装结构方面的丰富经验，通过胶囊的精确和有针对性的功能化，创造出具有开创性功能阵列的超分子胶囊。我的建议是在一个关键时刻提出的，寻求通过创建可编程和信息丰富的超分子系统来应对新出现的挑战。该奖学金将创建具有前所未有的专一性和受控定向运动的超分子结构，然后与合作者合作将这些应用于生物环境，旨在实现对生物医学科学的长期影响。

Supramolecular Chemistry is often inspired by the functionality and complexity of nature. Whilst great strides have been made towards achieving artificial analogues of biological molecular machines, synthetic systems have been unable to match the specificity and directionality vital to the concerted processes of biology. Here, I will develop new tools to endow artificial supramolecular systems with the functionality seen in their biological counterparts. In the first four years, I will create architectures with unprecedented target binding specificity, and systems able to transfer information across biologically-relevant membranes. In the following three years, I will collaboratively apply these in biological contexts, aiming to achieve long-term impact on biomedicine and synthetic biology by creating de novo catalytic enzyme analogues, enabling the design of synthetic cellular receptors, and generating targeted drug delivery vehicles. In the longer term, this proposal will provide new ways to repair and, eventually, replace, faulty biological systems, and so to treat intractable diseases. The complexity and functionality of biological systems is due to the information-richness of biomolecules, and their controlled distribution and motion. These properties allow demanding tasks to be completed; biomachines, such as ATP synthase, work in concert across membranes, maintaining homeostasis, and information-rich enzymes transform specific molecules using targeted interactions. In contrast, the current generation of supramolecular assemblies lack the targeted recognition present in nature, and are typically unable to work in concert, as their motion cannot be orientated. This research proposal will provide tools to bridge this gap, addressing unmet challenges in Supramolecular Chemistry. I will develop interlocked architectures whose localisation in membranes enables oriented motion, acting as novel analogues of transmembrane receptors such as GPCRs, and information-rich molecular capsules with targeted functions, able to mimic the binding specificity and catalytic function of enzymes.My proposal will, firstly, develop interlocked architectures that can embed into membranes (combining my expertise in artificial molecular machines and rotaxane formation, and expertise in membrane science at King's and the Crick) and transmit information from outside the compartment to the interior. This will enable modulation of the internal environment without the signal molecule having to pass the membrane, by physically coupling the two compartments. As such, I will create novel analogues of transmembrane signalling proteins. We will use this technology to create artificial analogues of cellular receptors, with potential applications in synthetic biology and the treatment of channelopathies such as Cystic Fibrosis and Dravet Syndrome. Secondly, this proposal will combine the information-density of biological systems with the well-defined cavity of metal-organic capsules to create supramolecular capsules with a ground-breaking array of functions, enabled by precise and targeted functionalisation of the capsule, exploiting my extensive experience of self-assembled architectures. My proposal comes at a critical juncture, seeking to address emerging challenges by creating programmable and information-rich supramolecular systems.This Fellowship will create supramolecular architectures with unprecedented specificity and controlled oriented directional motion, then work with collaborators to apply these in biological contexts, aiming to achieve long-term impact on biomedical science.