Energetics of the human Tel-22 quadruplex-telomestatin interaction: A molecular dynamics study
Energetics of the human Tel-22 quadruplex-telomestatin interaction: A molecular dynamics study
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DOI：
10.1021/jp7102676
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发表时间：
2008-06-05
影响因子：
3.3
通讯作者：
Maiti, Souvik
中科院分区：
文献类型：
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作者：
Agrawal, Saurabh;Ojha, Rajendra Prasad;Maiti, Souvik
端粒四链体的形成和稳定化已经显示出抑制端粒酶的活性，从而确立端粒DNA四链体作为癌症治疗干预的有吸引力的靶标。在这种情况下，端粒抑素，一个G-四链体特异性配体的结合和稳定的G-四链体，是非常感兴趣的知识的三维结构的端粒四链体和它的复合物在溶液中是一个先决条件，基于结构的合理的药物设计。在这里，我们报告了K+离子条件下人端粒四链体（AG（3）[T（2）AG（3）]（3））结构的相对稳定性及其与端粒抑制素的结合相互作用，通过分子动力学模拟和能量计算确定。能量学研究表明，在K+离子存在下，混合杂化型Tel-22四链体构象比其它构象更稳定。四链体-端粒抑制素相互作用的结合自由能表明1：2结合优于1：1结合。为了进一步证实我们的结果，我们还计算了与1：1和1：2结合模式相关的溶剂可及表面积（Δ SASA）和热容（Δ C-p）的变化。对四链体-端粒酶抑制素相互作用进行的广泛研究将有助于理解影响四链体-配体相互作用的参数，并将作为合理药物设计的平台。
The formation and stabilization of telomeric quadruplexes has been shown to inhibit the activity of telomerase, thus establishing telomeric DNA quadruplex as an attractive target for cancer therapeutic intervention. In this context, telomestatin, a G-quadruplex-specific ligand known to bind and stabilize G-quadruplex, is of great interest Knowledge of the three-dimensional structure of telomeric quadruplex and its complex with telomestatin in solution is a prerequisite for structure-based rational drug design. Here, we report the relative stabilities of human telomeric quadruplex (AG(3)[T(2)AG(3)](3)) structures under K+ ion conditions and their binding interaction with telomestatin, as determined by molecular dynamics simulations followed by energy calculations. The energetics study shows that, in the presence of K+ ions, mixed hybrid type Tel-22 quadruplex conformations are more stable than other conformations. The binding free energy for quadruplex-telomestatin interactions suggests that 1:2 binding is favored over 1:1 binding. To further substantiate our results, we also calculated the change in solvent-accessible surface area (Delta SASA) and heat capacity (Delta C-p) associated with 1:1 and 1:2 binding modes. The extensive investigation performed for quadruplex-telomestatin interaction will assist in understanding the parameters influencing the quadruplex-ligand interaction and will serve as a platform for rational drug design.