Structure and Stability of Higher-Order Human Telomeric Quadruplexes

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• 作者：Luigi Petraccone ; Charles Spink ; John O. Trent ; Nichola C. Garbett ; Chongkham S. Mekmaysy ; Concetta Giancola ; Jonathan B. Chaires
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：December 28, 2011
• 年：2011
• 卷：133
• 期：51
• 页码：20951-20961
• 全文大小：1012K
• 年卷期：v.133,no.51(December 28, 2011)
• ISSN：1520-5126

文摘

G-quadruplex formation in the sequences 5鈥?(TTAGGG)_n and 5鈥?TTAGGG)_nTT (n = 4, 8, 12) was studied using circular dichroism, sedimentation velocity, differential scanning calorimetry, and molecular dynamics simulations. Sequences containing 8 and 12 repeats formed higher-order structures with two and three contiguous quadruplexes, respectively. Plausible structures for these sequences were determined by molecular dynamics simulations followed by experimental testing of predicted hydrodynamic properties by sedimentation velocity. These structures featured folding of the strand into contiguous quadruplexes with mixed hybrid conformations. Thermodynamic studies showed the strands folded spontaneous to contain the maximum number contiguous quadruplexes. For the sequence 5鈥?TTAGGG)₁₂TT, more than 90% of the strands contained completely folded structures with three quadruplexes. Statistical mechanical-based deconvolution of thermograms for three quadruplex structures showed that each quadruplex melted independently with unique thermodynamic parmameters. Thermodynamic analysis revealed further that quadruplexes in higher-ordered structures were destabilized relative to their monomeric counterparts, with unfavorable coupling free energies. Quadruplex stability thus depends critically on the sequence and structural context.