Structure of Human Telomeric DNA in Crowded Solution

• Published in: Journal of the American Chemical Society 2011-06, Vol.133 (25), p.9824-9833
• Main Authors: Heddi, Brahim, Phan, Anh Tuân
• Format: Article
• Language: English
• Subjects: DNA - chemistry; G-Quadruplexes; Humans; Magnetic Resonance Spectroscopy; Molecular Dynamics Simulation; Nucleic Acid Conformation; Potassium; Solutions; Telomere - genetics
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja200786q

G-quadruplex structures formed by DNA at the human telomeres are attractive anticancer targets. Human telomeric sequences can adopt a diverse range of intramolecular G-quadruplex conformations: a parallel-stranded conformation was observed in the crystalline state, while at least four other forms were seen in K+ solution, raising the question of which conformation is favored in crowded cellular environment. Here, we report the first NMR structure of a human telomeric G-quadruplex in crowded solution. We show that four different G-quadruplex conformations are converted to a propeller-type parallel-stranded G-quadruplex in K+-containing crowded solution due to water depletion. This study also reveals the formation of a new higher-order G-quadruplex structure under molecular crowding conditions. Our molecular dynamics simulations of solvent distribution provide insights at molecular level on the formation of parallel-stranded G-quadruplex in environment depleted of water. These results regarding human telomeric DNA can be extended to oncogenic promoters and other genomic G-rich sequences.