Year: 2026
Type: preprint
Abstract: G-quadruplexes (G4s) are widely studied noncanonical nucleic-acid structures that carry important biological functions. Typically, G4s form from G-rich sequences containing at least four tracts of more than two consecutive guanines, yet a plethora of unconventional G4-forming sequences have been identified, including sequences that fold into G4s only under specific conditions. These G4 states remain poorly resolved. Here we identify dehydration-responsive left-handed G4s (drLHG4s), a class of left-handed G4 (LHG4) structures accessible under dehydrating conditions. Using d(GT) n repeats, we show that left-handed folding depends on repeat length, salt condition and solvent conditions. Systematic mutational analysis reveals a broader but register-constrained sequence space, while high-resolution crystal structures of d-GTGGTGTGTGGTG, a sequence that folded robustly under dehydrating conditions, establish a bulged LHG4 architecture and reveal a distinctive hydration sphere. We further show that selected peptides and a cationic zinc phthalocyanine derivative, ZnTEG Q PyrPc, containing four triethylene glycol methyl ether tails can induce LHG4 states. Together, our findings reveal a dehydration-responsive G4 landscape and expand the experimentally accessible sequence space of LHG4 folding.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Energy, University of Strathclyde, Swarthmore College, Government of the United Kingdom, UK Research and Innovation, South African Medical Research Council, Institut National de la Santé et de la Recherche Médicale, China Scholarship Council, Centre National de la Recherche Scientifique, Fondation de l'École Polytechnique, National Institutes of Health, Office of Science, Medical Research Council, National Institute of General Medical Sciences, Biological and Environmental Research, Research Ireland
OpenAlex ID: W7221822777