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。膜的这种细胞隔室化允许分离不兼容的催化条件。当试图将生物催化水溶液与在有机溶剂中优化的化学催化分析联系起来时，经常发生类似的不相容性。韦伯组中开发的分子信息继电器可以为此问题提供令人兴奋的解决方案。这些继电器沿多纳米距离传输信息，这使它们能够在水性和疏水环境中同时运行。[1]，[2]的核心是两亲α-氨基二氨基二糖（AIB）折叠剂，采用良好定义的螺旋构成。 。传入信息会导致N端的结构发生变化（例如，M到P螺旋开关），该结构已继电器到折叠剂的远端。韦伯（Webb）表明，这些折叠剂可以从水性化学信使深处传播到膜的疏水区域以产生光谱输出。现在，我们希望使用生物催化产生化学信使，并用化学分析代替光谱输出。结果将是一个信息继电器，通过在化学催化剂中诱导对映选择性来扩大酶的手性输出；产生合成信号级联。特纳实验室将通过筛选可以通过生物催化过程（例如通过激酶，脱氢酶等的作用。Webb和Turner以前发现南极脂肪酶B Hydrolyses RAC-Bocproome在水中的RAC-BOCPROOME提供了具有高对映选择性的BOC-D-PRO。[3]这是一个已知的活性信号分子，但是该酶尚未针对膜上的折叠剂进行筛选。类似的AIB折叠器可以在E.E. [4]的混合物在[4]中，替代方案包括分辨出的羧酸羧酸盐（将一种对映异构体转化为非结合产物，例如醛，酰胺或乳胶），或将脂质底物转化为手动羧酸盐的酶转化。信号级联的下一部分将使用AIB折叠剂，该折叠剂在其C末端带有N-杂环卡宾斯（NHC），该c-terminus允许访问有机金属的催化“写头”。第一代催化“写头”，即foldamer-rh（i）复合物，已在韦伯实验室中显示，以将酮降低到手性醇。需要开发更多的催化反应（例如炔烃的氢硅烷化）和其他催化写头，例如Ru（II）-NHC复合物，用于综合。学生将接受广泛的多学科培训。该项目将始于AIB折叠式 - 和金属材料复合物的化学合成，并分析其在有机溶剂中的催化性能，包括对低水平水的耐受性。同时，将进行配体筛选，并开发与磷脂囊泡兼容的酶促系统，并能够生成富含对映的羧酸酯。最后，将安装一个识别基序，并在囊泡中评估分子构建体的性能。该项目将化学分析与生物催化结合在一起，以创建协同的化学/生物催化级联。此外，学生将在韦伯当前由EPSRC资助的分子机器人技术研究中使用AIB折叠剂与PDRA紧密合作，并加强了这一领域的工作。