Balasubramanian Sangeetha, Senapati Sanjib
Department of Biotechnology, BJM School of Biosciences, Indian Institute of Technology Madras, Chennai 600 036, India.
J Phys Chem B. 2020 Dec 10;124(49):11055-11066. doi: 10.1021/acs.jpcb.0c04826. Epub 2020 Nov 25.
G-quadruplexes (GQs) are highly stable noncanonical forms of nucleic acids that are present in important genomic regions. The central core of the GQ is lined up by four closely spaced carbonyl groups from the G-quartets, and the resulting electrostatic repulsion is neutralized by the coordinating cations. In spite of several reports on GQ structure and cation-GQ interactions, the atomic- to molecular-level understanding of the ion dynamics and ion exchange in the GQ core is quite poor. Here, we attempt to elucidate the mechanism of Na and K binding to the GQ core and trace the exchange of these ions with the ions in bulk by means of all-atomic molecular dynamics (MD) simulations. One of the most studied GQs, telomeric G-quadruplex (OxyGQ), is taken as the representative GQ. Subsequently, umbrella sampling MD simulations were performed to elucidate the energetics of ion translocation from one end to the other end of the GQ central core. Our study highlights the importance of ion hydration for the uptake and correct positioning of the cations in the core. The free-energy landscape of ion transport has shown favorable in-plane binding of Na ions with GQ quartets, which matches very well with the crystal structure. The binding of K ions, on the other hand, was out-of-plane and its translocation required a larger barrier to cross.
G-四链体（GQs）是存在于重要基因组区域的高度稳定的非经典核酸形式。G-四链体的中心核心由来自G-四重体的四个紧密间隔的羰基排列而成，由此产生的静电排斥通过配位阳离子得以中和。尽管已有多篇关于G-四链体结构和阳离子-G-四链体相互作用的报道，但对G-四链体核心中离子动力学和离子交换的原子到分子水平的理解仍相当匮乏。在此，我们试图通过全原子分子动力学（MD）模拟来阐明钠和钾与G-四链体核心结合的机制，并追踪这些离子与本体相中离子的交换。研究最多的G-四链体之一，端粒G-四链体（OxyGQ），被用作代表性的G-四链体。随后，进行了伞形采样MD模拟，以阐明离子从G-四链体核心一端转移到另一端的能量学。我们的研究突出了离子水合对于阳离子在核心中的摄取和正确定位的重要性。离子传输的自由能态势表明，钠离子与G-四重体在平面内的结合较为有利，这与晶体结构非常吻合。另一方面，钾离子的结合是平面外的，其转移需要跨越更大的势垒。
