Tsvetkov Vladimir, Mir Bartomeu, Alieva Rugiya, Arutyunyan Alexander, Oleynikov Ilya, Novikov Roman, Boravleva Elizaveta, Kamzeeva Polina, Zatsepin Timofei, Aralov Andrey, González Carlos, Zavyalova Elena
Center for Mathematical Modeling in Drug Development, Sechenov First Moscow State Medical University, Moscow 119991, Russia.
Department of Cell Biology, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Moscow 119435, Russia.
Nucleic Acids Res. 2025 Jan 7;53(1). doi: 10.1093/nar/gkae1282.
Non-canonical nucleic acid structures play significant roles in cellular processes through selective interactions with proteins. While both natural and artificial G-quadruplexes have been extensively studied, the functions of i-motifs remain less understood. This study investigates the artificial aptamer BV42, which binds strongly to influenza A virus hemagglutinin and unexpectedly retains its i-motif structure even at neutral pH. However, BV42 conformational heterogeneity hinders detailed structural analysis. Molecular dynamics simulations and chemical modifications of BV42 helped us to identify a potential binding site, allowing for aptamer redesign to eliminate the conformational diversity while retaining binding affinity. Nuclear magnetic resonance spectroscopy confirmed the i-motif/duplex junction with the three-cytosine loop nearby. This study highlights the unique structural features of the functional i-motif and its role in molecular recognition of the target.
非经典核酸结构通过与蛋白质的选择性相互作用在细胞过程中发挥重要作用。虽然天然和人工G-四链体都已得到广泛研究，但i-基序的功能仍不太清楚。本研究调查了人工适配体BV42，它与甲型流感病毒血凝素紧密结合，并且出乎意料的是，即使在中性pH值下仍保留其i-基序结构。然而，BV42的构象异质性阻碍了详细的结构分析。BV42的分子动力学模拟和化学修饰帮助我们确定了一个潜在的结合位点，从而能够对适配体进行重新设计，在保留结合亲和力的同时消除构象多样性。核磁共振波谱证实了i-基序/双链体连接点以及附近的三胞嘧啶环。本研究突出了功能性i-基序的独特结构特征及其在靶标分子识别中的作用。
