Siebenmorgen Till, Zacharias Martin
Physics Department, Technical University of Munich, Garching, Germany.
Physics Department, Technical University of Munich, Garching, Germany.
Biophys J. 2017 Jun 6;112(11):2280-2290. doi: 10.1016/j.bpj.2017.04.036.
Telomeric DNA consists of tandem repeats of the sequence d(TTAGGG) that form G-quadruplex structures made of stacked guanines with monovalent cations bound at a central cavity. Although different ions can stabilize a G-quadruplex structure, the preferred bound ions are typically K or Na. Several different strand-folding topologies have been reported for Q-quadruplexes formed from telomeric repeats depending on DNA length and ion solution condition. This suggests a possible dependence of the ion selectivity of the central pore on the folding topology of the quadruplex. Molecular dynamics free energy perturbation has been employed to systematically study the relative affinity of the central quadruplex pore for different cation types and the associated energetic and solvation contributions to ion selectivity. The calculations have been performed on two different common quadruplex folding topologies. For both topologies, the same ion selectivity was found with a preference for K followed by Rb and Na, which agrees with the experimentally determined preference for most investigated quadruplexes. The selectivity is determined by a balance between attractive Coulomb interactions and loss of hydration but also modulated by van der Waals contributions. Specificity is mediated by the central guanines and no significant contribution of the nucleic acid backbone. The simulations indicate that different topologies might be stabilized by ions bound at the surface or alternative sites of the quadruplex because the ion specificity of the central pore does not depend on the strand folding topology.
端粒DNA由序列d(TTAGGG)的串联重复组成，这些重复序列形成了由堆叠的鸟嘌呤构成的G-四链体结构，一价阳离子结合在中央腔中。尽管不同的离子都可以稳定G-四链体结构，但优先结合的离子通常是K或Na。根据DNA长度和离子溶液条件，已经报道了由端粒重复序列形成的Q-四链体的几种不同的链折叠拓扑结构。这表明中央孔的离子选择性可能依赖于四链体的折叠拓扑结构。分子动力学自由能微扰已被用于系统地研究中央四链体孔对不同阳离子类型的相对亲和力以及对离子选择性的相关能量和溶剂化贡献。计算是在两种不同的常见四链体折叠拓扑结构上进行的。对于这两种拓扑结构，都发现了相同的离子选择性，优先选择K，其次是Rb和Na，这与大多数研究的四链体的实验确定的偏好一致。选择性由吸引性库仑相互作用和水合作用损失之间的平衡决定，但也受到范德华力贡献的调节。特异性由中央鸟嘌呤介导，核酸主链没有显著贡献。模拟表明，不同的拓扑结构可能由结合在四链体表面或其他位点的离子稳定，因为中央孔的离子特异性不依赖于链折叠拓扑结构。
