Zhou Jia-Kai, Yang Dah-Yen, Sheu Sheh-Yi
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Phys Chem Chem Phys. 2015 May 21;17(19):12857-69. doi: 10.1039/c5cp00378d.
G-quadruplexes are attractive drug targets in cancer therapy. Understanding the mechanisms of the binding-unbinding processes involving biomolecules and molecular recognition is essential for designing new drugs of G-quadruplexes. We performed steered molecular dynamics and umbrella sampling simulations to investigate the molecular mechanism and kinetics of ligand unbinding processes of the basket, propeller and hybrid G-quadruplex structures. Our studies of the ligand charge effect showed that Coulomb interaction plays a significant role in stabilizing the G-quadruplex structure in the unbinding process. The free energy profiles were carried out and the free energy changes associated with the unbinding process were computed quantitatively, whereas these results could help to identify accessible binding sites and transient interactions. The dynamics of the hydration shell water molecules around the G-quadruplex exhibits an abnormal Brownian motion, and the thickness and free energy of the hydration shell were estimated. A two-step relaxation scheme was theoretically developed to describe the kinetic reaction of BMVC and G-quadruplex interactions. Our computed results fall in a reasonable range of experimental data. The present investigation could be helpful in the structure-based drug design.
G-四链体是癌症治疗中具有吸引力的药物靶点。了解涉及生物分子和分子识别的结合-解离过程的机制对于设计新型G-四链体药物至关重要。我们进行了引导分子动力学和伞形抽样模拟，以研究篮状、螺旋桨状和混合G-四链体结构的配体解离过程的分子机制和动力学。我们对配体电荷效应的研究表明，库仑相互作用在解离过程中对稳定G-四链体结构起着重要作用。进行了自由能分布计算，并定量计算了与解离过程相关的自由能变化，而这些结果有助于识别可及的结合位点和瞬时相互作用。G-四链体周围水化层水分子的动力学表现出异常的布朗运动，并估计了水化层的厚度和自由能。从理论上开发了一种两步弛豫方案来描述BMVC与G-四链体相互作用的动力学反应。我们的计算结果落在实验数据的合理范围内。本研究可能有助于基于结构的药物设计。
