A G-rich sequence was designed to allow folding into either a stable parallel or hybrid-type topology. With the parent sequence featuring coexisting species, various related sequences with single and double mutations and with a shortened central propeller loop affected the topological equilibrium. Two simple modifications, likewise introduced separately to all sequences, were employed to lock folds into one of the topologies without noticeable structural alterations. The unique combination of sequence mutations, high-resolution NMR structural information, and the thermodynamic stability for both topological competitors identified critical loop residue interactions. In contrast to first loop residues, which are mostly disordered and exposed to solvent in both propeller and lateral loops bridging a narrow groove, the last loop residue in a lateral three-nucleotide loop is engaged in stabilizing stacking interactions. The propensity of single-nucleotide loops to favor all-parallel topologies by enforcing a propeller-like conformation of an additional longer loop is shown to result from their preference in linking two outer tetrads of the same tetrad polarity. Taken together, the present studies contribute to a better structural and thermodynamic understanding of delicate loop interactions in genomic and artificially designed quadruplexes, e.g. when employed as therapeutics or in other biotechnological applications.

中文翻译：

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通过环残基相互作用指导 G-四链体的折叠

富含 G 的序列旨在允许折叠成稳定的平行或混合型拓扑。对于具有共存物种的亲本序列，具有单突变和双突变以及缩短的中央螺旋桨环的各种相关序列影响拓扑平衡。两个简单的修改，同样分别引入所有序列，被用来将折叠锁定到一种拓扑结构中，而没有明显的结构改变。两个拓扑竞争者的序列突变、高分辨率 NMR 结构信息和热力学稳定性的独特组合确定了关键环残基相互作用。与第一环残基相反，后者在螺旋桨和桥接窄槽的横向环中大多是无序的并且暴露于溶剂，侧向三核苷酸环中的最后一个环残基参与稳定堆积相互作用。单核苷酸环倾向于通过强制一个额外的较长环的螺旋桨状构象来支持所有平行拓扑结构，这表明它们偏爱连接具有相同四分体极性的两个外部四分体。总之，目前的研究有助于更好地了解基因组和人工设计的四联体中微妙的环相互作用的结构和热力学，例如，当用作治疗或其他生物技术应用时。单核苷酸环倾向于通过强制一个额外的较长环的螺旋桨状构象来支持所有平行拓扑结构，这表明它们偏爱连接具有相同四分体极性的两个外部四分体。总之，目前的研究有助于更好地了解基因组和人工设计的四联体中微妙的环相互作用的结构和热力学，例如，当用作治疗或其他生物技术应用时。单核苷酸环倾向于通过强制一个额外的较长环的螺旋桨状构象来支持所有平行拓扑结构，这表明它们偏爱连接具有相同四分体极性的两个外部四分体。总之，目前的研究有助于更好地了解基因组和人工设计的四联体中微妙的环相互作用的结构和热力学，例如，当用作治疗或其他生物技术应用时。