"There is now increasing evidence that specific nucleic acid structures modulate gene expression levels both at the transcriptional and at the translational level. In particular, G-quadruplex (G4) structures are attractive targets for anticancer strategies, since several studies showed that their stabilization by ligands caused proliferation arrest, telomere deprotection and changes in gene expression. Understanding the structure-function relationships in G4 DNA and RNA requires innovative biophysical tools to probe the general and specific features of the structures adopted by a wide variety of sequences, their macromolecular assemblies, and their interactions with small molecules. I propose here to develop native mass spectrometry and ion mobility spectrometry as biophysical tools to probe small molecule ligand interactions with G4 structures. My recent work on small (~20-30 bases) G4 models demonstrated that MS is uniquely well suited to detect and quantify G4-drug interactions in a direct binding assay. The objective of the present project is now to characterize not only the binding affinity and specificity but also the binding mode of ligands for a variety of DNA and RNA targets. Ion mobility spectrometry will be crucial for studying the conformational adaptability of the target, and ligand-induced conformational changes. The model targets will vary in sequence, but also in size. Indeed, one still widely unaddressed challenge is to account for the flanking sequences that can form secondary structures and tertiary structures interacting with the G4 and, in the case of genomic non-B-DNA targets, to include the adjacent and competing double-stranded DNA. The biophysical approaches developed here for a specific purpose (G4 ligands) will also be widely applicable to other nucleic acid targets."