Helical foldamers with tunable channels for transmembrane water and ion transport

Descrizione del progetto

Strutture sintetiche migliorate per imitare i canali ionici e idrici biologici

Negli organismi superiori, le cellule sono circondate da membrane che le separano dall’ambiente esterno e mediano lo scambio di fluidi, elettroliti o proteine. Queste membrane sono tipicamente composte da proteine che fungono da canali in grado di aprirsi e chiudersi in risposta a ioni e molecole selettivi. La ricerca si è in gran parte concentrata sui canali ionici biologici ingegnerizzati per comprendere ulteriormente il loro meccanismo e come potrebbero potenzialmente trattare alcune malattie, come le canalopatie. Finanziato dal programma di azioni Marie Skłodowska-Curie, il progetto HeliTrans prevede di sintetizzare il primo canale ionico o idrico sintetico e unimolecolare. Il progetto sfrutterà i risultati precedenti nella progettazione di foldameri aromatici per migliorare la selettività dei canali ionici e idrici sintetici.

Obiettivo

The development of synthetic molecules capable of mimicking the modes of action of biological ion and water membrane channels is crucial to understand their mechanism and potentially to cure diseases (channelopathies) associated with their malfunctions. Synthetic transporters and channels that have already been reported so far, suffer from ill-defined structures or complex mechanisms that make it difficult to establish structure-property relationships in order to improve their efficiency and selectivity. This project aims at designing, synthesizing and studying the very first membrane spanning unimolecular synthetic ion or water channels in the form of long helically folded aromatic oligomers with suitably oriented binding sites at the inner rim. It builds upon earlier achievements in aromatic foldamer design concerning both molecular recognition in helical cavities, and the development of efficient solid phase synthetic methods (SPS) to access sequences longer than 40 units. About 40 units are predicted to fold in a 10-turn open-ended helix with a sizeable channel, covering a total height of ~35 Å, which is equivalent to the thickness of a lipid membrane. Such objects would be structurally stable and well-defined, amenable to structural fine-tuning by changing the composition of individual monomers one at a time, to modulate channel diameter and polar/apolar features. Their channeling behavior will be studied in vesicles and planar bilayers and will be correlated to their structure. Such correlation will allow, for the first time in the field, to build predictive design capabilities. This multidisciplinary project will enrich my strong background on artificial membrane channels with foldamer chemistry and should be decisive to help me reaching an independent academic research position.