Abstract：
Daunomycin is a widely used anticancer drug, yet the mechanism underlying how it binds to DNA remains contested. 469 all-atom trajectories of daunomycin binding to the DNA oligonucleotide d(GCG CAC GTG CGC) were collected using weighted ensemble (WE)-enhanced sampling. Mechanistic insights were revealed through analysis of the ensemble of trajectories. Initially, the binding process involves a ubiquitous hydrogen bond between the DNA backbone and the NH3+ group on daunomycin. During the binding process, most trajectories exhibited similar structural changes to DNA, including DNA base pair rise, bending, and minor groove width changes. Variability within the ensemble of binding trajectories illuminates differences in the orientation of daunomycin as it initially intercalates; around 10% of trajectories needed minimal rearrangement from intercalation to reaching the fully bound configuration, whereas most needed an additional 1-5 ns to rearrange. The results here emphasize the utility of generating an ensemble of trajectories to discern biomolecular binding mechanisms.
摘要：
道诺霉素是一种广泛使用的抗癌药物，然而，它与DNA结合的潜在机制仍然存在争议。使用加权集合（WE）增强的采样收集了469种与DNA寡核苷酸d（GCGCACGTGCGC）结合的道诺霉素的全原子轨迹。通过对轨迹集合的分析揭示了力学见解。最初，结合过程涉及DNA骨架和道诺霉素上的NH3+基团之间普遍存在的氢键。在绑定过程中，大多数轨迹表现出与DNA相似的结构变化，包括DNA碱基对上升,弯曲,和微小的凹槽宽度变化。结合轨迹集合内的可变性说明了道诺霉素最初嵌入时方向的差异；从嵌入到达到完全结合的构型，大约10％的轨迹需要最小的重排，而大多数需要额外的1-5ns来重新排列。此处的结果强调了生成轨迹集合以辨别生物分子结合机制的实用性。
