DNAFOLDIMS · Advanced mass spectrometry approaches to reveal nucleic acid folding energy landscapes

50 years after the discovery of the DNA double helix, the variety of structures that nucleic acids can adopt continues to surprise the scientific community. Specific structures and conformational changes are linked to important functions in cell regulation. Understanding the principles that govern how small molecules such as natural metabolites or synthetic drugs modulate the nucleic acid structures is of prime importance for molecular biology and pharmacology. The field however suffers from the lack of suitable experimental tools to monitor all assemblies and structures formed when a small molecule encounters its targets.The goal of my project is to develop unique mass spectrometry-based approaches to detect, quantify and characterize all these assemblies and structures. Our team’s strength will be to integrate a multidisciplinary approach, from physical and analytical chemistry to molecular biology. We will address the fundamentals of nucleic acid ionization and transfer in the gas phase, develop a unique instrumental setup combining mass spectrometry, ion mobility and circular dichroism ion spectroscopy, and apply these new approaches to biologically important nucleic acids, in order to reveal the mechanisms of ligand-induced conformational changes in important regulatory structures such as G-quadruplex or riboswitches.This research will also have broader impact, as the approaches and concepts developed here for nucleic acids will contribute fundamental advances in mass spectrometry, and will be transferrable to other supramolecular or biological complexes.