Design And Synthesis Of Foldamer-Based Potassium Ion Carriers

Potassium ion is the main cation in the cell,it plays an important role in maintaining the osmotic pressure of ions inside and outside the cell membrane,participating in signal transduction,and muscle contraction and other normal physiological activities.There are a large number of potassium channel proteins on the cell membrane,which can regulate the transmembrane behavior of potassium ions specifically,so as to ensure the life and health of cells.Abnormal function of these potassium channel proteins usually causes potassium channel diseases,such as epilepsy and long QT syndrome.At present,the use of biotechnology to control the transmembrane transport behavior of potassium ions in vivo is facing a great challenge.Therefore,the development of chemical means that can control potassium ions and thus regulate cell life activities is expected to provide a new method for the treatment of potassium channel disease,and is an important research topic in the field of biomedicine.So far,chemists have developed macroloops,artificial helices,peptides and other functional systems that promote potassium ion transmembrane,such as ion channels and molecular machines.However,the transport activity(EC50)of most artificial potassium ion transmembrane systems is not high,which restricts its application in vivo.Therefore,to design a bionic system of potassium ion transmembrane with high ion selectivity and high transport activity,and establish a transporter model different from ion channels,it is expected to develop a new molecular tool that can control potassium ion transmembrane transport in vivo.In this paper,we try to construct a transporter with the properties of potassium ion transmembrane transport,and study the properties of ion transport by focusing on the structural characteristics of the transporter structure,such as flexibility,rigidity and stability.The main research work includes two contents.One is to design and synthesize an ion transporter containing a flexible skeleton,and to study the effect of potassium ion complex pore structure on ion selectivity and transport efficiency.The second is to construct stable helical molecular capsule transporters by molecular folding,and to study the influence of the structure and stability of the inner helical cavity on ion recognition and transport efficiency.These studies help to understand the relationship between the structure and properties of the transporter cavity,and provide valuable information for the design of molecular tools to manipulate potassium ions efficiently across membranes.Specific work is as follows:1)Potassium ion transporters with flexible primitivesBased on the design of helical foldamer with the ability of selective recognition of potassium ion,a flexible methylene ether bridge containing potassium ion binding in the skeleton was prepared by multi-step chemical synthesis.The introduction of flexible methylene ether bridge makes it difficult for the transporters to form pre-organized pore structure and self-assemble to form transmembrane channels.The transport experiments with temperature-sensitive DPPC liposomes proved that the transporter(A)transported potassium ions across the membrane in an ion transport mode,excluding ion channels.It was found that the transporter containing flexible primitive can effectively bind potassium and sodium ions to form 1:1 complex.The results show that compared with rigid molecular skeleton,the presence of flexible elements changes the ion transport mode and significantly affects the ion selectivity and transport activity of potassium/sodium,confirming that the preorganized pore structure plays a central role in ion selectivity.These experimental results provide enlightening information for the design of transporter molecules.2)Helical foldamers with potassium ion transport propertiesTransporters need to bind and release ions in their functions.Studying the changes of cavity stability of artificial transporters to observe their ion transport properties is helpful to understand the influence of cavity structure stability on the ion transport function of artificial transporters.For this purpose,we construct aromatic foldamers(C and D)with different spiral lengths and internal cavities by molecular folding,wherein helical foldamer C is pentamer and foldamer D is heptamer.The crystal structure of helical foldamer D confirms the internal cavity structure and helical folding conformation,indicating the rationality of structural design.The temperature sensitive DPPC liposome transport experiments confirmed that both helical foldamer C and D transported potassium ions across membranes in ion transport mode,excluding ion channel mode.It is also found that both helical foldamer C and D exhibit ion binding ability,but their ion transport properties across membranes are significantly different.Among them,the helical transporter C can effectively assist potassium ion transmembrane at the concentration of 1 μM,and its potassium/sodium ion selectivity reaches 8.7.Compared with pentamer C,helical heptamer D has a more stable helical conformation,which is not conducive to ion binding and release,and it shows lower ion transport activity.These results show that the stability of the ion complex cavity significantly affects the transport activity of the transporter,and the increase of the stability of the cavity is not conducive to the rapid binding and release of ions.