Pavlin Matic, Herlah Barbara, Valjavec Katja, Perdih Andrej
Department of Catalysis and Chemical Reaction Engineering, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.
Theory Department, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.
Comput Struct Biotechnol J. 2023 Jul 22;21:3746-3759. doi: 10.1016/j.csbj.2023.07.019. eCollection 2023.
Type IIA DNA topoisomerases are complex molecular nanomachines that manage topological states of the DNA molecule in the cell and play a crucial role in cellular processes such as cell division and transcription. They are also established targets of cancer chemotherapy. Starting from the available crystal structure of a fully catalytic topoisomerase IIA homodimer from , we constructed three states of this molecular motor primarily changing the configurations of the DNA segment bound in the DNA gate and performed μs-long all-atom molecular simulations. A comprehensive analysis revealed a sliding motion within the DNA gate and a teamwork between the N-gate and DNA gate that may be associated with the necessary molecular events that allow passage of the T-segment of DNA. The observed movement of the ATPase dimer relative to the DNA domain was reflected in different interaction patterns between the K-loops of the transducer domain and the B-A-B form of the bound DNA. Based on the obtained results, we mapped simulated configurations to the structures in the proposed catalytic cycle through which type IIA topoisomerases exert their function and discussed the possible transition events. The results extend our understanding of the mechanism of action of type IIA topoisomerases and provide an atomistic interpretation of some of the observed features of these molecular motors.
IIA型DNA拓扑异构酶是复杂的分子纳米机器，负责管理细胞中DNA分子的拓扑状态，并在细胞分裂和转录等细胞过程中发挥关键作用。它们也是癌症化疗已确定的靶点。从一种来自[具体来源未给出]的完全催化性拓扑异构酶IIA同型二聚体的可用晶体结构出发，我们构建了这种分子马达的三种状态，主要改变结合在DNA门中的DNA片段的构型，并进行了微秒级的全原子分子模拟。全面分析揭示了DNA门内的滑动运动以及N门和DNA门之间的协同作用，这可能与允许DNA的T片段通过的必要分子事件相关。观察到的ATP酶二聚体相对于DNA结构域的运动反映在转导结构域的K环与结合DNA的B - A - B形式之间不同的相互作用模式中。基于获得的结果，我们将模拟构型映射到IIA型拓扑异构酶发挥其功能所经历的拟议催化循环中的结构，并讨论了可能的转变事件。这些结果扩展了我们对IIA型拓扑异构酶作用机制的理解，并为这些分子马达的一些观察到的特征提供了原子层面的解释。
