title: G-quadruplex conformation and dynamics are determined by loop length and sequence.
abstract: The quadruplex forming G-rich sequences are unevenly distributed throughout the human genome. Their enrichment in oncogenic promoters and telomeres has generated interest in targeting G-quadruplex (GQ) for an anticancer therapy. Here, we present a quantitative analysis on the conformations and dynamics of GQ forming sequences measured by single molecule fluorescence. Additionally, we relate these properties to GQ targeting ligands and G4 resolvase 1 (G4R1) protein binding. Our result shows that both the loop (non-G components) length and sequence contribute to the conformation of the GQ. Real time single molecule traces reveal that the folding dynamics also depend on the loop composition. We demonstrate that GQ-stabilizing small molecules, N-methyl mesoporphyrin IX (NMM), its analog, NMP and the G4R1 protein bind selectively to the parallel GQ conformation. Our findings point to the complexity of GQ folding governed by the loop length and sequence and how the GQ conformation determines the small molecule and protein binding propensity.
authors.affiliation: Bioengineering Department, University of Illinois, 1304 W. Springfield Ave., Urbana, IL 61801, USA.
authors.forename: Ramreddy
authors.initials: R
authors.lastname: Tippana
authors.affiliation: Bioengineering Department, University of Illinois, 1304 W. Springfield Ave., Urbana, IL 61801, USA.
authors.forename: Weikun
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Bioengineering Department, University of Illinois, 1304 W. Springfield Ave., Urbana, IL 61801, USA Biophysics and Computational Biology, 1110 W. Green St., Urbana, IL 61801, USA Institute for Genomic Biology, 1206 Gregory Drive, Urbana, IL 61801, USA Physics Frontier Center (Center of Physics for Living Cells), University of Illinois, 1110 W. Green St., Urbana, IL 61801, USA smyong@illinois.edu.
authors.forename: Sua
authors.initials: S
authors.lastname: Myong
mesh_terms: D001483:Base Sequence; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D054856:G-Quadruplexes; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008652:Mesoporphyrins / Q000378:metabolism; D016615:Telomere / Q000737:chemistry
chemical_list: D008024:Ligands; D008652:Mesoporphyrins; C065420:N-methylmesoporphyrin IX; D004247:DNA; D053487:DEAD-box RNA Helicases