Despite the simplicity of the short telomeric G4 forming sequences, G4 structures have an intrinsic conformational polymorphism, due to differing backbone orientations and type of internal loops (13,14). The prevalence of one particular conformation in solution is dictated by factors such as counter-ion type and concentration, solvent composition, as well as the length of the DNA sequence and the type of terminal flanking nucleotides (15). Depending on these factors several stable folded G4 structures have been identified for the human telomeric sequence (16–20). This multifactorial nature of G4s makes their folding highly complex, possibly involving a number of stable intermediate states and misfolded species and is beyond a simple two-state approximation (21). Several studies have found G4 folding to occur through a simple sequential pathway, involving up to two intermediate states (21–26), however recently more complex folding scenarios have started to emerge (27–30). One important bottleneck in uncovering the G4 folding pathway remains the structural identification of the different folded states appearing during the folding process.