Direct Quantification of Loop Interaction and 蟺鈥撓€ Stacking for G-Quadruplex Stability at the Submolecular Level

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• 作者：Chiran Ghimire ; Soyoung Park ; Keisuke Iida ; Philip Yangyuoru ; Haruka Otomo ; Zhongbo Yu ; Kazuo Nagasawa ; Hiroshi Sugiyama ; Hanbin Mao
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：November 5, 2014
• 年：2014
• 卷：136
• 期：44
• 页码：15537-15544
• 全文大小：515K
• ISSN：1520-5126

文摘

The well-demonstrated biological functions of DNA G-quadruplex inside cells call for small molecules that can modulate these activities by interacting with G-quadruplexes. However, the paucity of the understanding of the G-quadruplex stability contributed from submolecular elements, such as loops and tetraguanine (G) planes (or G-quartets), has hindered the development of small-molecule binders. Assisted by click chemistry, herein, we attached pulling handles via two modified guanines in each of the three G-quartets in human telomeric G-quadruplex. Mechanical unfolding using these handles revealed that the loop interaction contributed more to the G-quadruplex stability than the stacking of G-quartets. This result was further confirmed by the binding of stacking ligands, such as telomestatin derivatives, which led to similar mechanical stability for all three G-quartets by significant reduction of loop interactions for the top and bottom G-quartets. The direct comparison of loop interaction and G-quartet stacking in G-quadruplex provides unprecedented insights for the design of more efficient G-quadruplex-interacting molecules. Compared to traditional experiments, in which mutations are employed to elucidate the roles of specific residues in a biological molecule, our submolecular dissection offers a complementary approach to evaluate individual domains inside a molecule with fewer disturbances to the native structure.