Conformational heterogeneity observed in simulations of a pyrene-substituted DNA.
Conformational heterogeneity observed in simulations of a pyrene-substituted DNA.
复制标题
芘取代 DNA 模拟中观察到的构象异质性。
DOI：
10.1021/ja026825l
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发表时间：
2002
影响因子：
15
通讯作者：
Simmerling,Carlos
中科院分区：
文献类型：
--
作者：
Cui,Guanglei;Simmerling,Carlos
先前对具有芘取代的碱基的DNA系统进行的NMR研究没有观察到涉及位于芘5'的腺嘌呤的NOE，因此腺嘌呤的构象在所得的精细结构家族中定义不佳。然而，化学位移数据表明，AT碱基对可能存在。我们已经进行了完全不受限制的分子动力学模拟，从几个成员的家庭结构，这些模拟支持存在的AT碱基对这一地区。在显式和隐式溶剂中进行了模拟，在所有情况下，每个收敛到腺嘌呤和碱基配对的反或顺式构象。在这些模拟过程中，观察到大的和戏剧性的构象变化，表明在高度密集的DNA内部复杂的构象变化的途径。我们的分析揭示了这些顺式和反式构象的能量差异不大，与标准DNA（在没有相邻芘的情况下）进行的控制计算相反。虽然在标准模拟中没有观察到构象之间的相互转换，但使用局部增强的采样方法直接模拟可逆的反/顺式交换。在非芘对照序列中未观察到交换。总之，这些结果表明，增加的灵活性引入作为芘取代的结果，提供了一个解释，是与现有的实验数据一致。这些结果增加了我们的乐观，在原子细节的模拟可能会提供准确的模型，在复杂的系统中的实验观察。
NMR studies previously carried out for a DNA system with a pyrene-substituted base did not observe NOEs involving the adenine located 5‘ to the pyrene, and thus the conformation of the adenine was poorly defined in the resulting family of refined structures. However, chemical shift data suggested that an AT base pair may be present. We have carried out fully unrestrained molecular dynamics simulations starting from several members of the family of structures, and these simulations support the existence of an AT base pair for this region. Simulations in both explicit and implicit solvent were carried out, with each converging to either anti or syn conformation for adenine and base pairing in all cases. During these simulations, large and dramatic conformational changes are observed that suggest pathways for complex conformational changes in the highly packed DNA interior. Our analysis reveals little difference in the energies of these syn and anti conformations, in contrast to control calculations carried out for standard DNA (in the absence of a neighboring pyrene). While no interconversion between the conformations was observed in standard simulations, reversible anti/syn exchange was directly simulated using the locally enhanced sampling approach. No exchange was seen in the non-pyrene control sequence. Together, these results suggest that an increased flexibility is introduced as a consequence of the pyrene substitution, offering an explanation that is consistent with the available experimental data. These results increase our optimism that simulations in atomic detail may provide accurate models for experimental observations in complex systems.