Pump up the volume: Foldamers as molecular amplifiers

提高音量：折叠器作为分子放大器

• 批准号: 2466761
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2466761
• 关键词: Pump; up; volume; Foldamers; molecular

different compartments. This cellular compartmentalisation by membranes permits the separation of incompatible catalytic conditions. A similar incompatibility often occurs when attempting to link aqueous biocatalysis with chemocatalysis that has been optimised in organic solvents. Molecular information relays developed in the Webb group could provide an exciting solution to this problem. These relays transmit information along multi-nanometre distances, which allows them to operate simultaneously in aqueous and hydrophobic environments.[1],[2] At their core is an amphiphilic alpha-aminoisobutyric acid (Aib) foldamer that adopts well-defined helical conformations. Incoming information causes a change in structure at the N-terminus (e.g. an M to P helicity switch) that is relayed to the far end of the foldamer. Webb has shown these foldamers can relay chiral information from an aqueous chemical messenger deep into the hydrophobic region of a membrane to produce a spectroscopic output. We now wish to produce chemical messengers using biocatalysis and to replace the spectroscopic output with chemocatalysis. The outcome will be an information relay that amplifies the chiral output from an enzyme by inducing enantioselectivity in a chemocatalyst; producing a synthetic signalling cascade. The Turner lab will provide the first part of the signalling cascade, by screening for potential ligands (carboxylates, phosphates) that can be produced by biocatalytic processes, e.g. by the action of kinases, dehydrogenases etc. Webb and Turner previously found that Candida antarctica lipase B hydrolyses rac-BocProOMe in water to give Boc-D-Pro with high enantioselectivity.[3] This is a known active signalling molecule, but this enzyme has not yet been screened against membrane-embedded foldamers. Similar Aib foldamers can report on the e.e. of mixtures produced through organocatalysis,[4] so alternatives include the kinetic resolution of racemic carboxylates (transformation of one enantiomer into a non-binding product such as an aldehyde, amide or lactone) or the enzymatic transformation of achiral substrates into chiral carboxylates. The next part of the signalling cascade will use Aib foldamers that bear N-heterocyclic carbenes (NHCs) at their C-terminus, which permits access to organometallic catalytic "write heads". The first generation of catalytic "write heads", foldamer-Rh(I) complexes, have been shown in the Webb lab to reduce ketones to chiral alcohols. More catalytic reactions need to be developed (e.g. alkyne hydrosilylation) and other catalytic write-heads, such as Ru(II)-NHC complexes for ROMP, synthesised.The student will receive broad multidisciplinary training. The project will start with the chemical synthesis of Aib foldamer-organometallic complexes and analysis of their catalytic performance in organic solvents, including tolerance to low levels of water. In parallel, ligand screening will be performed and enzymatic systems developed that are compatible with phospholipid vesicles and able to generate enantioenriched carboxylate. Finally a recognition motif will be installed, and the performance of the molecular construct assessed when in vesicles.This project combines chemocatalysis with biocatalysis to create a synergistic chemo/biocatalysis cascade. Furthermore the student will work closely with PDRAs using Aib foldamers in Webb's current EPSRC-funded research in molecular robotics, bolstering efforts in this area.

不同的隔间这种通过膜的细胞区室化允许分离不相容的催化条件。当试图将水性生物催化与在有机溶剂中优化的化学催化联系起来时，经常发生类似的不相容性。韦伯小组开发的分子信息中继器可以为这个问题提供一个令人兴奋的解决方案。这些继电器沿沿着多纳米的距离传输信息，这使得它们能够在水性和疏水性环境中同时工作。[1][2]在它们的核心是一个两亲性α-氨基异丁酸（Aib）折叠体，其采用明确定义的螺旋构象。传入的信息导致N-末端的结构变化（例如M到P螺旋度转换），其被中继到折叠体的远端。韦伯已经证明，这些折叠体可以将水溶性化学信使的手性信息传递到膜的疏水区域深处，从而产生光谱输出。我们现在希望使用生物催化产生化学信使，并用化学催化取代光谱输出。结果将是一个信息中继，通过诱导化学催化剂中的对映选择性来放大酶的手性输出;产生合成信号级联。Turner实验室将提供信号级联的第一部分，通过筛选可通过生物催化过程产生的潜在配体（羧酸盐、磷酸盐），例如通过激酶、脱氢酶等的作用。WebB和Turner先前发现，南极假丝酵母脂肪酶B在水中水解rac-BocProOMe，得到具有高对映体选择性的Boc-D-Pro。[3]这是一种已知的活性信号分子，但这种酶尚未针对膜嵌入的折叠体进行筛选。类似的Aib折叠体可以在e.e.通过有机催化产生的混合物，[4]因此替代方案包括外消旋羧酸盐的动力学拆分（将一种对映体转化为非结合产物，例如醛、酰胺或内酯）或将非手性底物酶促转化为手性羧酸盐。信号级联的下一部分将使用Aib折叠体，其在其C-末端带有N-杂环卡宾（NHC），这允许进入有机金属催化“写头”。第一代催化“写头”，折叠体-Rh（I）络合物，已经在Webb实验室中显示出将酮还原为手性醇。需要开发更多的催化反应（如炔氢化硅烷化）和其他催化写头，如用于ROMP的Ru（II）-NHC络合物，合成。学生将接受广泛的多学科培训。该项目将从Aib折叠体-有机金属配合物的化学合成开始，并分析其在有机溶剂中的催化性能，包括对低水含量的耐受性。与此同时，将进行配体筛选，并开发与磷脂囊泡相容并能够产生对映体富集的羧酸盐的酶系统。最后，将安装一个识别基序，并评估分子构建体在囊泡中的性能。该项目将化学催化与生物催化相结合，创造一个协同的化学/生物催化级联。此外，学生将在Webb目前EPSRC资助的分子机器人研究中使用Aib折叠体与PDRA密切合作，以支持这一领域的工作。