CNR-IOM, Unità Operativa di Supporto SLACS, c/o Dipartimento di Fisica, Università di Cagliari, s.p. Monserrato-Sestu km 0.7, I-09042 Monserrato, Italy.
Inorg Chem. 2012 Feb 20;51(4):2046-57. doi: 10.1021/ic201659v. Epub 2012 Jan 30.
Molecules that selectively recognize DNA mismatches (MMs) play a key role as nucleic acids probes and as chemotherapeutic agents. Metallo-insertors bind to the minor groove (mG) of double strand (ds) DNA, expelling the mismatched base pairs and acting as their π-stacking replacement. In contrast, metallo-intercalators bind to the major groove (MG) of ds DNA and π-stack to adjacent base pairs. In this study we focused on structural and energetic properties of Δ-Rh(bpy)(2)(chrysi) (1), Δ-Ru(bpy)(2)(ddpz) (2), and Δ-Ru(bpy)(2)(eilatin) (3) as prototypical examples of metallo-insertors and intercalators. For all molecules we characterized both insertion and intercalation into a DNA dodecamer via force field based molecular dynamics (MD) and hybrid quantum-classical (QM/MM) MD simulations. A structural analysis of the 1-3/DNA noncovalent adducts reveals that the insertion provokes an untwist of the DNA, an opening of the mG and of the phosphate backbone in proximity of the mismatch, while the intercalation induces smaller changes of these structural parameters. This behavior appears to be correlated with the size of the inserting/intercalating ligand in proximity of the metal coordination site. Moreover, our simulations show that the different selectivity of 1 toward distinct MM types may be correlated with the thermodynamic stability of the MMs in the free DNA and with that of the corresponding insertion adduct. Understanding the factors which tune a specific insertion is of crucial importance for designing specific luminescent probes that selectively recognize MMs, as well as for developing more effective anticancer drugs active in MM repair of deficient cells lines.
选择性识别 DNA 错配 (MM) 的分子在作为核酸探针和化学治疗剂方面发挥着关键作用。金属插入剂结合到双链 (ds) DNA 的小沟 (mG)，排出错配碱基对并充当它们的 π-堆积替代品。相比之下，金属嵌入剂结合到 ds DNA 的大沟 (MG) 并 π-堆积到相邻的碱基对。在这项研究中，我们专注于 Δ-Rh(bpy)(2)(chrysi) (1)、Δ-Ru(bpy)(2)(ddpz) (2) 和 Δ-Ru(bpy)(2)(eilatin) (3) 作为金属插入剂和嵌入剂的典型范例的结构和能量特性。对于所有分子，我们通过基于力场的分子动力学 (MD) 和混合量子经典 (QM/MM) MD 模拟来表征它们在 DNA 十二聚体中的插入和嵌入。对 1-3/DNA 非共价加合物的结构分析表明，插入会引起 DNA 的未扭曲、mG 的打开以及错配附近磷酸骨架的打开，而嵌入会引起这些结构参数的较小变化。这种行为似乎与金属配位位点附近插入/嵌入配体的大小相关。此外，我们的模拟表明，1 对不同 MM 类型的不同选择性可能与游离 DNA 中 MM 的热力学稳定性以及相应插入加合物的稳定性相关。了解调节特定插入的因素对于设计选择性识别 MM 的特定发光探针以及开发更有效的在 MM 修复缺陷细胞系中具有活性的抗癌药物至关重要。
