Artificial Ion Channels Constructed By Molecular Folding Strategies

The ion transmembrane transport system is essential to maintain the normal operation of life activities as the "gatekeepers" of the cell membrane,selectively transporting ions or proteins closely related to physiological activities and maintaining the dynamic homeostasis of the cell.However,Dysfunction of natural ion channel proteins can lead to serious ion channel diseases such as neurological disorders(generalised epilepsy or hemiplegic migraine),respiratory disorders(cystic fibrosis),endocrine disorders(diabetes Mellitus),etc.The complex structure of natural channel proteins has limited the study of ion channel diseases.Fortunately,data of channel protein crystal has been reported in a resolved manner under the development of technological tools.High-resolution cryo-electron microscopy data of channel proteins has given us an explanation of the structural details of natural ion channels.In that case people have a deeper understanding of the transport mechanism of natural ion channels.More and more structures of natural ion channels have been reported.Scientists are learning to mimic natural ion channels and creating a wide variety of artificial ion channels by a variety of non-covalent bonds such as hydrogen bonds,electrostatic interactions,metal coordination,host-guest interactions and ion-? interactions.As an alternative to natural ion channels,artificial ion channels not only help people to better understand how ion transport works,but also been used as drugs for the treatment of ion channel-based diseases.Although artificial ion channels have shown excellent biocompatibility and ion transport properties in vitro experiments,the high selectivity and gating characteristics of natural ion channels are difficult for synthesis systems to mimic.In order to better mimic natural channel proteins and reveal the natural laws of ion transport,our group has developed a sustainable artificial ion channel transport system.With its unique modifiable cavity,adjustable cavity size and abundant building blocks,the channel has unlimited potential in mimicking natural ion channels.The main objective of this thesis is to mimic the properties of natural channel proteins and use the strategy of molecular folding to construct ion transmembrane channel compounds,so as to enrich the topology of the artificial ion channel transport system and explore the ion transport efficiency and ion selectivity.1.Biomimetic ion channels with enhanced sodium ion selectivityWe have studied natural potassium and sodium ion channels and found that the natural potassium ion channel cavity size is smaller than that of natural sodium ion cavity.This is due to the fact that sodium ions have a smaller radius as well as a stronger effective electric field which is more attractive to water.Therefore,in solution,sodium ions can form larger water shells under hydration.In the process of ion transport there is a process of dehydration,that is,the stripping of the binding between ions and water.The potassium ions are well matched to the four oxygen atoms in the ion channel selector,thus forming coordination bonds to compensate for the energy of dehydration.However,the smaller size of the sodium ion does not perfectly match with the potassium ion channel,and the stronger relative hydration energy of the sodium ion requires more coordination bonds to compensate for the dehydration energy.Based on the highly selective potassium ion channels reported by our group,we studied the difference in cavity size of natural potassium and sodium ion channel selective filter.On the basis of retaining the effective ion binding sites,we introduced the self-designed motifs to expand the cavity size of the channels and realize the enhancement of sodium ion selectivity.2.Artificial double-cavity cation channelsInspired by the structure of chloride channels(st Cl C)that have the ability to transport ions as channel dimers,we have attempted to abandon the traditional idea of constructing single-cavity ion channels to develop double-pore ion channels.Doublepore ion channel is a new type of ion channel in which two single pore channels are organically integrated using a bridging unit.Based on the experience of our group,we screened different bridging units and finally selected the rigid bi-oxadiazole unit as the main building block for the synthesis of double-pore ion channels.In the presence of the bi-oxadiazole,the double-pore molecule exists in an S-shaped conformation.Under the action of its own ?-? stacking,the double-pore molecule can self-assemble within the membrane to form a double-pore ion channel with two identical hollow ion transport paths.Unlike our previous understanding of single-cavity artificial ion channels,doublecavity ion channels are undoubtedly new in terms of ion channel transport modes.Our development of such double-pore ion channels not only enriches our artificial ion transport system,but also provides a structural basis for the development of new porous ion channels,and provides a good model to explain the natural channel transport mechanism at the chemical level.3.Design and synthesis of helical topological anion channelsUrea units,as an electron-withdrawing group,can provide hydrogen bonds to bind anions efficiently,so they are often used to design synthetic anion transporters.Then,we attempted to introduce urea unit into helical topological channels.By using a molecular folding strategy,we arranged urea unit within a three-dimensional helical skeleton regularly,and successfully synthesized the first artificial anion helical channel containing urea unit.Through liposomal bionic functional tests,we investigated the effect of the hydrogen-bond donor-rich helical channels on ion transport as well as ion selectivity.The introduction of the urea unit not only enriches the helical sequence substitution,but also creates a completely new helical topology?These novel ion transmembrane channels are the expressions of our learning outcome from natural ion channels.They can not only enrich the topology of traditional ion transmembrane systems,but also provide us with unique ideas for future functional applications.