NCN (MINIATURA): Photoswitchable ligands for riboswitches (2018/02/X/NZ1/01468); 21670 PLN 2018-2019. PI: F.Stefaniak

Ribonucleic acid (RNA) molecules play pivotal roles in living organisms. They are involved in a variety of biological processes: they transmit genetic information, they sense and communicate responses to cellular signals, and even catalyze chemical reactions. The cellular and molecular functions of RNAs depend on the structure of the ribonucleotide chain and on interactions with other molecules, which are defined by the ribonucleotide sequence. Structures and functions of RNAs are often modulated by small chemical molecules, including naturally occurring molecules as well as compounds obtained by synthetic organic chemistry. Many RNA molecules are known or predicted targets of small molecule drugs, and the continuous discovery of new functional RNAs involved in various biomedically important processes increases the demand on the development of new small molecules targeting RNA.

Riboswitches represent RNA molecules, whose structures can be modulated upon small molecule binding. They typically occur within the protein-non-coding parts of messenger RNA (mRNA) and regulate the translation of the protein-coding parts. Riboswitches can directly form complexes with small molecules and, in this way, regulate gene function. Among natural ligands recognized by riboswitches are metabolites, divalent cations, and second messengers. As riboswitches are common in bacteria and rarely occur in eukaryotes, they are emerging as a potential target for new and selective antibacterial drugs.

Photoswitches are one type of molecular machines that can be switched between at least two distinct thermodynamically stable forms by the application of an external stimulus, e.g., light.

In this project, we combine these two concepts and develop and test photoswitchable small molecules as ligands binding to riboswitches. The aim of our research is to test the mechanism of triggering conformational change of RNA by the light-induced structural change of a bound ligand. In this project we combine computational methods (like molecular docking, Monte Carlo simulations) with experimental validation (like SHAPE footprinting, X-ray crystallography).

This project is carried out in collaboration with Dr. W. Szymański from the University of Groningen and the University Medical Center Groningen.