Wang Zhiguo, Chen Ruping, Hou Ling, Li Jianfeng, Liu Jun-Ping
Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, 311121, China,
Protein Cell. 2015 Jun;6(6):423-33. doi: 10.1007/s13238-015-0155-3. Epub 2015 Apr 18.
Telomere assumes intra-molecular G-quadruplex that is a significant drug target for inhibiting telomerase maintenance of telomeres in cancer. Metal cations have been recognized as playing important roles in stabilizing G-quadruplex, but their binding processes to human telomeric G-quadruplex remain uncharacterized. To investigate the detailed binding procedures, molecular dynamics simulations were conducted on the hybrid [3 + 1] form-one human telomeric intra-molecular G-quadruplex. We show here that the binding of a potassium ion to a G-tetrad core is mediated by two alternative pathways. Principal component analysis illustrated the dominant concerted motions of G-quadruplex occurred at the loop domains. MM-PBSA calculations revealed that binding was energetically favorable and driven by the electrostatic interactions. The lower binding site was found more constructive favorable for binding. Our data provide useful information on a potassium-mediated stable structure of human telomeric intra-molecular G-quadruplex, implicating in ion disorder associated conformational changes and targeted drug design.
端粒呈现分子内G-四链体结构，这是抑制癌症中端粒酶维持端粒的一个重要药物靶点。金属阳离子在稳定G-四链体中发挥着重要作用，但其与人端粒G-四链体的结合过程仍未明确。为了研究详细的结合过程，我们对[3 + 1]杂合形式的人端粒分子内G-四链体进行了分子动力学模拟。我们在此表明，钾离子与G-四联体核心的结合由两条不同的途径介导。主成分分析表明，G-四链体的主要协同运动发生在环结构域。MM-PBSA计算表明，结合在能量上是有利的，且由静电相互作用驱动。发现较低的结合位点对结合更有利。我们的数据为钾介导的人端粒分子内G-四链体稳定结构提供了有用信息，涉及离子紊乱相关的构象变化和靶向药物设计。
