Pump up the volume: Foldamers as molecular amplifiers

不同的车厢。这种通过膜进行的细胞分隔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，通常会发生类似的不相容。Webb小组开发的分子信息继电器可以为这个问题提供一个令人兴奋的解决方案。这些继电器沿多纳米距离传输信息，这使它们能够在水和疏水环境中同时运行。[1]、[2]其核心是采用明确螺旋构象的两亲性α-氨基异丁酸(AIB)分子。传入的信息导致N末端的结构改变(例如，M到P的螺旋度开关)，该结构被传递到折叠器的远端。韦伯已经证明，这些折叠体可以将来自水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来生产化学信使，并用化学催化来取代光谱输出。其结果将是一个信息传递，通过在化学催化剂中诱导对映体选择性，放大酶的手性输出；产生合成信号级联。特纳实验室将提供信号级联反应的第一部分，通过筛选生物催化过程中可能产生的潜在配体(羧酸盐、磷酸盐)，例如通过激酶、脱氢酶等的作用。Webb和Turner之前发现，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，但这种酶尚未被筛选出对抗膜嵌入的折叠体。类似的AIB文件夹可以在e.e上报告。对于通过有机催化产生的混合物，[4]因此，替代方法包括外消旋羧酸盐的动力学拆分(将一个对映体转化为非结合产物，如醛、酰胺或内酯)，或将非手性底物转化为手性羧酸盐。信号级联的下一部分将使用C端带有N-杂环卡宾(NHC)的AIB折叠体，这允许访问有机金属催化“写入头”。韦伯实验室已经展示了第一代催化“写头”--FolDamer-Rh(I)络合物，它可以将酮还原为手性醇。需要开发更多的催化反应(例如，炔氢硅氢化)和其他催化笔头，如用于ROMP的Ru(II)-NHC络合物的合成。学生将接受广泛的多学科培训。该项目将从化学合成AIB有机金属络合物开始，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，并开发与磷脂微囊兼容并能够产生对映体富集羧酸盐的酶系统。最后，将安装一个识别基序，并评估分子结构在囊泡中的性能。该项目将化学催化和生物催化相结合，以创建协同化学/生物催化级联。此外，在Webb目前由EPSRC资助的分子机器人研究中，该学生将使用AIB折叠器与PDRA密切合作，支持这一领域的努力。

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.