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

非规范 G 四链体的稳定相互作用和合理设计

• 批准号: 410497337
• 负责人: Professor Dr. Klaus Weisz
• 金额: --
• 依托单位: Arbeitskreis Analytische Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/410497337?language=en
• 关键词: Stabilizing; interactions; rational; design; non

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.

由于其可能的生物学作用，G-四链(G4S)作为药物干预的新靶点引起了人们的极大兴趣。此外，G4S还被越来越多地用作各种技术应用中的强大工具，例如作为适配子、传感器或电子开关。它们的高度多态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，由于对导致富含G的序列进入特定折叠的关键相互作用缺乏了解，任意四链拓扑的合理设计和基于序列的结构预测受到限制，特别是对于以G柱断裂为特征的非规范G4结构。在一个正在进行的项目的继续中，将通过优化G-Track插入序列来研究到规范和非规范结构的竞争折叠，以选择定义的结构。重点将放在经常出现的具有V形或Snapback环路的非规范拓扑上。高分辨率核磁共振结构的确定与量热法得出的热力学稳定性相结合，有望为能够加强和稳定相应G4物种的关键相互作用提供有价值的见解。一种用于引导折叠的有吸引力的工具包括当在目标G4的结构重排时形成的四链-双链(Q-D)界面。在这里，在Q-D连接处的特定配体的结合，也是基因组中假定的识别热点，可以额外地移动平衡，从而被用于诱导替代折叠。预计这些发现将促进结构预测和规范的、特别是非规范的G4结构基序的合理设计。