DNA刚性及其构象转变的温度相关性研究

Nucleic acids play pivotal roles not only in genetic information storage but also in various biological functions. Because many molecular processes in living cell involving DNA depend on the nanoscale properties of the double helix, the structure, conformational transition and rigidity of DNA are of great important in understanding the DNA-protein interactions and the critical role of DNA in the processes of the cell cycle, and have long been concerned by the chemical, physical, and biological fields. DNA is a double-stranded molecule constructed by nucleotides through hydrogen bonding, considering that biological organisms exist over a broad temperature range of -15℃ to +120℃, the entropy plays a significant role in the structure and double-helical elasticity, both inside the base pair and between successive base pairs, and even the conformational transition. That is, the conformation and rigidity of DNA is temperature dependent. In the present proposal, we intend to understand the effect of temperature induced entropy on the DNA rigidity by studying the local structure and conformational transition, and the rigidity of the whole DNA double strands, through all atom molecular dynamics of DNA oligomers at a time scale of microsecond and a length scale of up to 100 base pairs. The expected results and conclusions will deepen our understanding of the DNA rigidity and conformational transitions, and even the activities of DNA in cellular mechanisms.

作为生物体的遗传物质，DNA构象转变和柔顺性是化学、物理和生命科学领域关注的重要科学问题。在纳米尺度上研究DNA的结构特性和柔顺性对了解DNA与蛋白质的相互作用，以及DNA在细胞周期活动中的参与机制非常重要。DNA是由碱基对通过氢键互补配对形成的双链生物大分子。由于生命活动的环境温度跨越从-15℃到+120℃的范围，DNA的这种结构特殊性，使温度导致的熵效应对DNA的分子结构及构象转变有显著的影响。也就是说，DNA的构象和柔顺性具有很强的温度依赖性。本申请将采用全原子分子动力学模拟方法，在大体系、长时间尺度上研究DNA局部构象转变及链刚性，考察温度导致的熵效应对DNA局部结构的影响，并探究DNA局构象转变对DNA整体柔顺性的影响，从而尝试对DNA柔顺性的温度效应做出比较全面的了解。预期研究结果将加深对DNA分子构象转变及其链刚性的理解,有助于更加全面深入地理解细胞活动中DNA的参与机制。

通过全原子分子动力学模拟，发现1-2个螺旋周期长度的DNA是偏离蠕虫链理想模型的，这种偏离是由DNA骨架静电排斥作用导致的；骨架中性化DNA模型研究表明DNA骨架静电排斥作用对其刚性的贡献是序列长度相关的；骨架静电排斥对DNA持久长度的贡献约为10%，符合Odijk、Skolnick和Fixman (OSF)的理论预测。球形纳米粒子表面接枝DNA的构象和位阻效应导致界面DNA链替换反应的“OFF/ON”开关效应；通过理论模拟结合实验研究，我们构建了基于球状核酸的DNA探针；通过理论模拟，深入探讨了DNA链间复杂相互作用对DNA泄漏反应和球状核酸系统稳定性的影响，实现了DNA链替换催化循环反应驱动的多级球状核酸组装反应体系。.项目执行期间，发表SCI论文12篇，其中JACS一篇。