Molecular dynamics simulations of the 136 unique tetranucleotide sequences of DNA oligonucleotides. II: Sequence context effects on the dynamical structures of the 10 unique dinucleotide steps
Molecular dynamics simulations of the 136 unique tetranucleotide sequences of DNA oligonucleotides. II: Sequence context effects on the dynamical structures of the 10 unique dinucleotide steps
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DOI：
10.1529/biophysj.105.067397
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发表时间：
2005-12-01
影响因子：
3.4
通讯作者：
Varnai, P
中科院分区：
文献类型：
--
作者：
Dixit, SB;Beveridge, DL;Varnai, P
报道了包括水和反离子在内的包含所有136个独特的四核苷酸碱基对步骤的B-DNA低聚物上的分子动力学(MD)模拟。目的是获得每个病例至少两个副本的计算动态结构，使用结果来检查关于MD在DNA上的收敛和动态稳定性的问题，并确定序列上下文效应对所有独特的二核苷酸步骤的意义。这些信息对理解序列对DNA结构的影响是必不可少的，并对DNA结构生物学中的各种问题有影响。对39个DNA寡聚体中的136例进行了计算，这些寡聚体含有重复的四核苷酸序列，两端都有GC对，每个DNA寡聚体的总长度为15个核苷酸对。所有的模拟都是使用定义良好的最先进的MD协议、Amber程序套件和parm94力场进行的。在之前的一篇文章中(Beveridge等人2004年。生物物理学杂志。87：3799-3813)，描述了研究设计、仿真协议的细节和信息学问题。在所有10个独特的序列环境中，给出了d(CpG)步长的15 ns MD轨迹的初步结果。结果表明，对于这一步骤，序列上下文影响很小，但揭示了在这段轨迹上，DNA上的MD受到糖-磷酸骨架扭转角α和伽马的惊人持续的协同转变的影响。在这篇文章中，我们详细分析了整个轨迹数据库和各种构象亚态的出现及其对上下文效应研究的影响。分析揭示了DNA结构依赖于序列的动力学趋势和经历转变的趋势之间可能的直接对应关系，这种转变使DNA处于非标准构象亚态。观察到的不同侧翼序列的碱基阶跃螺旋面参数分布的平均值有时相差一个标准差，表明序列效应的程度可能是显著的。观察结果表明，像CpG这样的柔性二核苷酸的影响可能超出直接碱基邻域。这些结果总体上为了解MD对DNA的影响以及DNA的序列相关的动态结构特征提供了新的见解。
Molecular dynamics ( MD) simulations including water and counterions on B-DNA oligomers containing all 136 unique tetranucleotide basepair steps are reported. The objective is to obtain the calculated dynamical structure for at least two copies of each case, use the results to examine issues with regard to convergence and dynamical stability of MD on DNA, and determine the significance of sequence context effects on all unique dinucleotide steps. This information is essential to understand sequence effects on DNA structure and has implications on diverse problems in the structural biology of DNA. Calculations were carried out on the 136 cases embedded in 39 DNA oligomers with repeating tetranucleotide sequences, capped on both ends by GC pairs and each having a total length of 15 nucleotide pairs. All simulations were carried out using a well-defined state-of-the-art MD protocol, the AMBER suite of programs, and the parm94 force field. In a previous article (Beveridge et al. 2004. Biophysical Journal. 87: 3799-3813), the research design, details of the simulation protocol, and informatics issues were described. Preliminary results from 15 ns MD trajectories were presented for the d(CpG) step in all 10 unique sequence contexts. The results indicated the sequence context effects to be small for this step, but revealed that MD on DNA at this length of trajectory is subject to surprisingly persistent cooperative transitions of the sugar-phosphate backbone torsion angles alpha and gamma. In this article, we report detailed analysis of the entire trajectory database and occurrence of various conformational substates and its impact on studies of context effects. The analysis reveals a possible direct correspondence between the sequence-dependent dynamical tendencies of DNAstructure and the tendency to undergo transitions that "trap'' them in nonstandard conformational substates. The difference in mean of the observed basepair step helicoidal parameter distribution with different flanking sequence sometimes differs by as much as one standard deviation, indicating that the extent of sequence effects could be significant. The observations reveal that the impact of a flexible dinucleotide such as CpG could extend beyond the immediate basepair neighbors. The results in general provide new insight into MD on DNA and the sequence-dependent dynamical structural characteristics of DNA.