The investigation of the G-quadruplex aptamer selectivity to Pb²⁺ ion: a joint molecular dynamics simulation and density functional theory study

The aptamers with the ability to form a G-quadruplex structure can be stable in the presence of some ions. Hence, study of the interactions between such aptamers and ions can be beneficial to determine the highest selective aptamer toward an ion. In this article, molecular dynamics (MD) simulations and quantum mechanics (QM) calculations have been applied to investigate the selectivity of the T30695 aptamer toward Pb²⁺ in comparison with some ions. The Free Energy Landscape (FEL) analysis indicates that Pb²⁺ has remained inside the aptamer during the MD simulation, while the other ions have left it. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding energies prove that the conformational stability of the aptamer is the highest in the presence of Pb²⁺. According to the compaction parameters, the greatest compressed ion-aptamer complex, and hence, the highest ion-aptamer interaction have been induced in the presence of Pb²⁺. The contact maps clarify the closer contacts between the nucleotides of the aptamer in the presence of Pb²⁺. The density functional theory (DFT) results show that Pb²⁺ forms the most stable complex with the aptamer, which is consistent with the MD results. The QM calculations reveal that the N-H bonds and the O…H distances are the longest and the shortest, respectively, in the presence of Pb²⁺. The obtained results verify that the strongest hydrogen bonds (HBs), and hence, the most compressed aptamer structure are induced by Pb²⁺. Besides, atoms in molecules (AIM) and natural bond orbital (NBO) analyses confirm the results. Communicated by Ramaswamy H. Sarma能够形成G-四链体（G-quadruplex）结构的适配体（aptamer）在部分离子存在的条件下可保持稳定。因此，研究此类适配体与离子之间的相互作用，有助于筛选出对某一离子选择性最优的适配体。本文采用分子动力学（molecular dynamics, MD）模拟与量子力学（quantum mechanics, QM）计算，探究了T30695适配体相较于其他离子对铅离子（Pb²+）的选择性。自由能景观（Free Energy Landscape, FEL）分析结果显示，在MD模拟过程中，Pb²+始终留存于适配体内部，而其余离子则脱离了适配体。分子力学泊松-玻尔兹曼表面积（Molecular Mechanics Poisson-Boltzmann Surface Area, MM-PBSA）结合能计算证实，适配体在Pb²+存在时的构象稳定性最高。基于压缩参数分析，在Pb²+存在的条件下，离子-适配体复合物的压缩程度最高，因此离子与适配体间的相互作用也最强。接触图谱表明，在Pb²+存在时，适配体的核苷酸之间的接触更为紧密。密度泛函理论（density functional theory, DFT）结果显示，Pb²+与适配体形成的复合物最为稳定，这与MD模拟结果相符。QM计算结果显示，在Pb²+存在的条件下，N-H键键长最长，而O…H键距最短。所得结果证实，Pb²+可诱导形成最强的氢键（hydrogen bonds, HBs），进而得到压缩程度最高的适配体结构。此外，原子分子理论（atoms in molecules, AIM）与自然键轨道（natural bond orbital, NBO）分析也验证了上述结论。本文由Ramaswamy H. Sarma转交。