Solution structure and dynamics of a complex between DNA and the antitumor bisnaphthalimide LU-79553: intercalated ring flipping on the millisecond time scale.
Solution structure and dynamics of a complex between DNA and the antitumor bisnaphthalimide LU-79553: intercalated ring flipping on the millisecond time scale.
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DNA 与抗肿瘤双萘二甲酰亚胺 LU-79553 复合物的溶液结构和动力学：毫秒时间尺度的插环翻转。
作者：
Gallego,J;Reid,BR
利用核磁共振波谱实验和分子动力学相结合的方法，我们分析了双萘亚胺类药物LU-79553与DNA双链d(ATGCAT)2之间的络合物的结构和动力学。Lu-79553是一种与DNA结合的拓扑异构酶II抑制剂，对其他药物无效的人类实体肿瘤特别有效。我们发现药物的两个萘酰亚胺发色团在DNA六核苷酸的TPG和CPA步骤处插入，主要与相反链上的嘌呤G和A碱基堆积。3，7-重氮烯连接体位于DNA分子的主槽中，它的两个氨基氢键连接到与对称相关的鸟嘌呤碱基上。出乎意料的是，我们检测到了药物−DNA复合体中两个等价的和插入状态的萘酰亚胺环之间的前所未有的交换过程。相互转化过程通过旋转翻环进行，两个环的活化能为22千卡·摩尔-1，不影响药物的氨基烷基连接区。在36°C(1800 S-1)的化学位移时间尺度上，交换速率是中到快的，而在2°C(20 S-1)的化学位移时间尺度上，交换速度很慢。基于核磁共振数据和时间平均受限分子动力学模拟，我们还观察到药物连接物在皮秒时间尺度上的有限灵活性。讨论了−LU-79553复合体的结构和动力学特征对双萘亚胺类药物结合特异性和抗肿瘤活性的影响。
Using a combination of nuclear magnetic resonance (NMR) spectroscopy experiments and molecular dynamics, we have analyzed the structure and dynamics of a complex between the bisnaphthalimide drug LU-79553 and the DNA duplex d(ATGCAT)2. LU-79553 is a DNA-binding topoisomerase II inhibitor that is particularly effective against human solid tumors that are refractory to other drugs. We have found that the two naphthalimide chromophores of the drug bisintercalate at the TpG and CpA steps of the DNA hexanucleotide, stacking mainly with the purine G and A bases from opposite strands. The 3,7-diazanonylene linker lies in the major groove of the DNA molecule, with its two amino groups hydrogen-bonded to the symmetry-related guanine bases. Unexpectedly, we have detected an unprecedented exchange process between two equivalent and intercalated states of the naphthalimide rings in the drug−DNA complex. The interconversion process takes place by rotational ring flipping, has an activation energy of 22 kcal mol-1for the two rings, and does not affect the aminoalkyl linker region of the drug. The exchange rate is intermediate to fast on the chemical shift time scale at 36 °C (1800 s-1) but slow at 2 °C (20 s-1). We have also observed limited flexibility for the drug linker on the picosecond time scale on the basis of NMR data and a time-averaged restrained molecular dynamics simulation. The implications of the structural and dynamic features of the DNA−LU-79553 complex on the binding specificity and on the antitumor activity of bisnaphthalimide agents are discussed.