Stabilizing interactions and rational design of non-canonical G-quadruplexes

由于其可能的生物学作用，g -四联体（G4s）作为药物干预的新靶点引起了相当大的兴趣。此外，G4s也越来越多地被用作各种技术应用中的强大工具，例如适配体、传感器或电子开关。它们高度多态的特性为它们的特定识别和功能优化提供了极好的机会。然而，由于缺乏对驱动g -富序列进入特定褶皱的关键相互作用的理解，任意四重拓扑的合理设计和基于序列的结构预测受到限制，特别是对于具有破碎g列的非规范G4结构。作为一个正在进行的项目的延续，将通过优化g束干预序列来选择定义的结构来研究规范和非规范结构的竞争性折叠。重点将放在经常出现的非规范拓扑与v形或回圈。高分辨率核磁共振结构的测定与量热衍生的热力学稳定性相结合，有望对能够加强和稳定相应G4物质的关键相互作用提供有价值的见解。一种有吸引力的用于引导褶皱的工具包括四工双工（Q-D）界面，当结构重排到目标G4时形成。在这里，特定配体在Q-D连接处的结合，也作为基因组内假定的识别热点，可能额外地改变平衡，从而用于诱导替代折叠。研究结果有望促进规范和非规范G4结构基序的结构预测和合理设计。

Because of their possible biological role, G-quadruplexes (G4s) have attracted considerable interest as novel targets for pharmaceutical interventions. Additionally, G4s have also been increasingly employed as powerful tools in various technological applications, e.g., as aptamers, sensors, or electronic switches. Their highly polymorphous nature offers excellent opportunities for their specific recognition and functional optimization. However, due to poor understanding of critical interactions that drive a G-rich sequence into a particular fold, the rational design of arbitrary quadruplex topologies and sequencebased structural predictions are restricted, especially for noncanonical G4 structures featuring broken G-columns. In continuation of an ongoing project, competitive folding to canonical and noncanonical structures will be studied through the optimization of G-tract intervening sequences to select for defined structures. Emphasis will be placed on frequently occurring non-canonical topologies with Vshaped or snapback loops. The determination of high-resolution NMR structures combined with calorimetry-derived thermodynamic stabilities is expected to give valuable insight into critical interactions that are able to enforce and stabilize corresponding G4 species. An attractive tool for guiding a fold includes quadruplex-duplex (Q-D) interfaces when formed upon structural rearrangements to the target G4. Here, binding of specific ligands at the Q-D junction, also serving as putative recognition hotspots within the genome, may additionally shift equilibria and thus be employed for inducing alternative folds. Findings are expected to promote both structure predictions and the rational design of canonical and in particular non-canonical G4 structural motifs.