DNA curvature is the result of a combination of both intrinsic features of the double helix and external distortions introduced by the environment and the binding of proteins or drugs. The propensity of certain double-stranded DNA (dsDNA) sequences to bend is essential in crucial biological processes, such as replication and transcription, in which proteins are known to either recognize noncanonical DNA conformations or promote their formation upon DNA binding. Trabectedin (Yondelis®) is a clinically used antitumor drug which, following covalent bond formation with the 2-amino group of guanine, induces DNA curvature and enhances the circularization ratio, upon DNA ligation, of several dsDNA constructs but not others. By means of unrestrained molecular dynamics simulations using explicitly solvated all-atom models, we rationalize these experimental findings in structural terms and shed light on the crucial, albeit possibly underappreciated, role played by T4 DNA ligase in stabilizing a bent DNA conformation prior to cyclization. Taken together, our results expand our current understanding on how DNA shape modification by trabectedin may affect both the sequence-specific recognition by transcription factors to promoter sites and RNA polymerase II binding.

DNA 弯曲是双螺旋的内在特征和环境引入的外部扭曲以及蛋白质或药物结合的结果。某些双链 DNA (dsDNA) 序列的弯曲倾向在关键的生物过程中至关重要，例如复制和转录，其中已知蛋白质要么识别非规范 DNA 构象，要么在 DNA 结合后促进它们的形成。Trabectedin (Yondelis®) 是一种临床上使用的抗肿瘤药物，在与鸟嘌呤的 2-氨基形成共价键后，在 DNA 连接时诱导 DNA 弯曲并提高环化率，但不包括其他一些 dsDNA 构建体。通过使用明确溶剂化的全原子模型进行无限制的分子动力学模拟，我们在结构方面对这些实验结果进行了合理化，并阐明了 T4 DNA 连接酶在环化前稳定弯曲 DNA 构象方面发挥的关键作用，尽管可能未被充分认识。总之，我们的结果扩展了我们目前对 trabectedin 修饰 DNA 形状如何影响转录因子对启动子位点的序列特异性识别和 RNA 聚合酶 II 结合的理解。