Human DNA topoisomerase IIα is a biological nanomachine that regulates the topological changes of the DNA molecule and is considered a prime target for anticancer drugs. Despite intensive research, many atomic details about its mechanism of action remain unknown. We investigated the ATPase domain, a segment of the human DNA topoisomerase IIα, using all-atom molecular simulations, multiscale quantum mechanics/molecular mechanics (QM/MM) calculations, and a point mutation study. The results suggested that the binding of ATP affects the overall dynamics of the ATPase dimer. Reaction modeling revealed that ATP hydrolysis favors the dissociative substrate-assisted reaction mechanism with the catalytic Glu87 serving to properly position and polarize the lytic water molecule. The point mutation study complemented our computational results, demonstrating that Lys378, part of the important QTK loop, acts as a stabilizing residue. The work aims to pave the way to a deeper understanding of these important molecular motors and to advance the development of new therapeutics.

中文翻译：

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人DNA拓扑异构酶IIαATP酶域ATP水解的催化机制

人类 DNA 拓扑异构酶 IIα 是一种生物纳米机器，可调节 DNA 分子的拓扑变化，被认为是抗癌药物的主要靶点。尽管进行了深入研究，但有关其作用机制的许多原子细节仍然未知。我们使用全原子分子模拟、多尺度量子力学/分子力学 (QM/MM) 计算和点突变研究研究了人类 DNA 拓扑异构酶 IIα 的一个片段 ATP 酶结构域。结果表明，ATP 的结合会影响 ATPase 二聚体的整体动力学。反应建模表明，ATP 水解有利于解离底物辅助反应机制，催化 Glu87 用于正确定位和极化裂解水分子。点突变研究补充了我们的计算结果，证明重要的 QTK 循环的一部分 Lys378 充当稳定残基。这项工作旨在为更深入地了解这些重要的分子马达铺平道路，并推动新疗法的发展。