Helical foldamers with tunable channels for transmembrane water and ion transport

Descripción del proyecto

Estructuras sintéticas mejoradas para imitar los canales iónicos y de agua biológicos

En los organismos superiores, las células están rodeadas por membranas que las separan del entorno exterior y median el intercambio de líquidos, electrolitos o proteínas. Estas membranas suelen estar compuestas por proteínas que actúan como canales que se abren y cierran en respuesta a moléculas e iones selectivos. La investigación se ha centrado en gran medida en canales iónicos biológicos modificados para comprender mejor su mecanismo y cómo podrían tratar ciertas enfermedades, como las canalopatías. El objetivo del proyecto HeliTrans, financiado por las Acciones Marie Skłodowska-Curie, es sintetizar el primer canal unimolecular iónico o de agua sintético. El proyecto se basará en logros anteriores en el ámbito del diseño de plegómeros aromáticos para mejorar la selectividad de los canales iónicos y de agua sintéticos.

Objetivo

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.