Nedělníková Andrea, Stadlbauer Petr, Otyepka Michal, Kührová Petra, Paloncýová Markéta
Regional Center of Advanced Technologies and Materials, Czech Advanced Technology and Research Institute (CATRIN), Palacký University Olomouc, Olomouc, Czech Republic.
Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic.
J Comput Chem. 2025 Jan 30;46(3):e70035. doi: 10.1002/jcc.70035.
Doxorubicin (DOX) is a widely used chemotherapeutic agent known for intercalating into DNA. However, the exact modes of DOX interactions with various DNA structures remain unclear. Using molecular dynamics (MD) simulations, we explored DOX interactions with DNA duplexes (dsDNA), G-quadruplex, and nucleosome. DOX predominantly stacks on terminal bases of dsDNA and occasionally binds into its minor groove. In the G-quadruplex, DOX stacks on planar tetrads but does not spontaneously intercalate into these structures. Potential of mean force calculations indicate that while intercalation is the most energetically favorable interaction mode for DOX in dsDNA, the process requires overcoming a significant energy barrier. In contrast, DOX spontaneously intercalates into bent nucleosomal DNA, due to the increased torsional stress. This preferential intercalation of DOX into regions with higher torsional stress provides new insights into its mechanism of action and underscores the importance of DNA tertiary and quaternary structures in therapies utilizing DNA intercalation.
阿霉素（DOX）是一种广泛使用的化疗药物，以嵌入DNA而闻名。然而，DOX与各种DNA结构相互作用的确切模式仍不清楚。我们使用分子动力学（MD）模拟研究了DOX与DNA双链体（dsDNA）、G-四链体和核小体的相互作用。DOX主要堆积在dsDNA的末端碱基上，偶尔会结合到其小沟中。在G-四链体中，DOX堆积在平面四联上，但不会自发嵌入这些结构。平均力势计算表明，虽然嵌入是DOX在dsDNA中能量上最有利的相互作用模式，但该过程需要克服一个显著的能量障碍。相比之下，由于扭转应力增加，DOX会自发嵌入弯曲的核小体DNA中。DOX优先嵌入扭转应力较高区域的现象为其作用机制提供了新的见解，并强调了DNA三级和四级结构在利用DNA嵌入的治疗中的重要性。
