Hydrogen-deuterium exchange mass spectrometry of nucleic acids – DNA-HDXMS

Hydrogen-deuterium exchange mass spectrometry (HDX/MS) is a popular analytical tool to study proteins dynamics, but in the field of nucleic acids, in-solution HDX/MS is currently not exploited. However, preliminary results show that nucleic acids are amenable to HDX/MS, opening new avenues to explore their structure, dynamics, and nucleic acid-protein interactions from the two sides of the coin: the protein and the nucleic acid. The project will lay the groundwork that will allow interpreting the results in terms of equilibria and dynamics, by establishing the fundamentals of nucleic acids HDX/MS kinetics. We also will develop analytical tools to perform native top-down HDX/MS experiments that would combine HDX to native MS separation (by mass and shape) and MS/MS fragmentation to obtain nucleotide-level rates. Finally, we will explore applications in life sciences (G-quadruplex dynamics and interactions, and quality control of potential oligonucleotide-based therapeutics).