Chemistry Department, Indian Institute of Science Education and Research, Pune-411021, India.
J Phys Chem B. 2012 Oct 11;116(40):12208-12. doi: 10.1021/jp307911r. Epub 2012 Oct 1.
DNA intercalation, a biophysical process of enormous clinical significance, has surprisingly eluded molecular understanding for several decades. With appropriate configurational restraint (to prevent dissociation) in all-atom metadynamics simulations, we capture the free energy surface of direct intercalation from minor groove-bound state for the first time using an anticancer agent proflavine. Mechanism along the minimum free energy path reveals that intercalation happens through a minimum base stacking penalty pathway where nonstacking parameters (Twist→Slide/Shift) change first, followed by base stacking parameters (Buckle/Roll→Rise). This mechanism defies the natural fluctuation hypothesis and provides molecular evidence for the drug-induced cavity formation hypothesis. The thermodynamic origin of the barrier is found to be a combination of entropy and desolvation energy.
DNA 插入，一种具有巨大临床意义的生物物理过程，令人惊讶的是，几十年来一直未能从分子水平上得到理解。在全原子元动力学模拟中施加适当的构象约束（以防止解离），我们首次使用抗癌药物普乐沙福捕获了直接插入从小沟结合态的自由能表面。沿着最小自由能路径的机制表明，插入是通过一个最小的碱基堆积罚分途径发生的，其中非堆积参数（Twist→Slide/Shift）首先发生变化，然后是碱基堆积参数（Buckle/Roll→Rise）。该机制违背了自然波动假说，并为药物诱导腔形成假说提供了分子证据。发现障碍的热力学起源是熵和去溶剂化能的组合。
