National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI 1000 Ljubljana, Slovenia.
J Chem Inf Model. 2022 Aug 22;62(16):3896-3909. doi: 10.1021/acs.jcim.2c00303. Epub 2022 Aug 10.
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.
人类 DNA 拓扑异构酶 IIα 是一种调控 DNA 分子拓扑变化的生物纳米机器，被认为是抗癌药物的主要靶点。尽管进行了深入的研究，但该分子的作用机制仍有许多原子细节尚不清楚。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，对人类 DNA 拓扑异构酶 IIα 的 ATP 酶结构域进行了研究。结果表明，ATP 的结合会影响 ATP 酶二聚体的整体动力学。反应建模揭示了 ATP 水解有利于具有催化 Glu87 适当定位和极化裂解水分子的解联底物辅助反应机制。点突变研究补充了我们的计算结果，表明 QTK 环的一部分重要残基 Lys378 作为稳定残基发挥作用。这项工作旨在为深入了解这些重要的分子马达铺平道路，并推进新疗法的开发。
