SQSig · Oligo-Squaramide Rigid-Rods for Artificial Transmembrane Signaling

Oligo-Squaramide Rigid-Rods for Artificial Transmembrane Signaling

Conformational change relayed over several nanometers is central to the function of many proteins. For example, G-protein coupled receptors (GPCRs) are transmembrane proteins that are used by cells to transmit information through their membranes and are responsible for some of the most important biological functions, such as sight and taste. Many GPCRs bind a ligand to their extracellular region, which provokes a conformational change and initiates a biological process inside the cell. The number of existing synthetic systems able to transfer conformational information across several nanometres is scarce. Exploring new designs can lead to applications in a wide range of contexts. Replicating allosteric regulation mechanisms could allow researchers to bypass endogenous signaling pathways in cells, a key target in medicinal chemistry, and will provide important communication tools for the development of molecular robots and fully synthetic cells. Such systems can be the basis of the materials and therapies of the future, and will use artificial communication relays, for example, to share information between different compartments or to interconnect different events within molecular factories. Moreover, a detailed understanding of the self-assembly properties and mode of operation of new molecular systems is crucial for scientific progress. The main objective of this project was to exploit the self-assembly properties of squaramides (SQs) to create an artificial relay of information. Monomeric SQs form ribbons with all the SQs oriented in the same direction. We designed a scaffolded oligo-SQ array that would form intramolecular hydrogen-bonded ribbons aligned in either one direction or the opposite one. Inverting the directionality of the terminal SQ of the ribbon would initiate a domino effect that would switch the orientation of the whole array. Upon functionalization, binding of an external ligand to the squaramide in one terminus would switch the directionality of the entire SQ-ribbon and provoke a spectroscopic response at the other end of the relay. Thus, this system would represent a synthetic GPCR, able to transmit conformational information across its linear structure, and with the potential to perform artificial signal transduction in bilayer membranes. Conclusions of the action: During this project, a multi-SQ hydrogen-bond relay has been arrayed along a rigid rod oligo(phenylene-ethynylene) (OPE) scaffold. The rigid rod dictates the length of the SQ information relay and prevents its folding and structural collapse. The relay adopts either a parallel or an antiparallel orientation relative to the scaffold; the preferred orientation can be dictated by a director group at one end. Installing a proton-responsive director in a 2 nm long SQ relay permitted multiple reversible changes in relay orientation in response to protonation/deprotonation signals. Moreover, a chemical fuel also acted as a signal, affording the first example of a molecular communication relay operating under out-of-equilibrium conditions.

Data: CORDIS, © European Union