RNA:DNA杂交结构是单链RNA与模板链DNA杂交形成的非标准核酸结构，也是R-loop结构的重要组成部分，具有转录调控和复制启动等多种生物功能，且以RNA作诱导的基因药物通过与标靶DNA形成较为稳定的杂交结构可抑制基因的表达。研究RNA:DNA杂交碱基对的热力学和动力学对杂交结构生物功能的理解、相关基因调控及基因药物的设计具有重要意义。目前实验测定杂交碱基对的热力学和动力学参数极其匮乏。所以，本项目中，申请人拟拓展已建立的统计力学和过渡态理论并结合分子动力学模拟等方法，得到杂交碱基对的热力学和动力学参数，揭示开关动力学微观机制，并进一步研究近邻碱基效应和溶液环境的影响，分析物理机制，为预测复杂杂交结构及稳定性和动力学行为提供依据。同时分析ssDNA对杂交结构及R-loop结构稳定性的影响，有助于从原子层面深入理解杂交结构与疾病诱导之间的关联，为进一步探索基因药物设计等方面提供理论依据。

RNA:DNA hybrids is a non-standard nucleic acid structure formed by hybridization of single-strand RNA with template-strand DNA. It is also an important part of the R-loop structure and has many biological functions, such as transcription regulation and replication initiation. Using RNA as guide, the genetic drug inhibits gene expression through forming a stable RNA:DAN hybrid structure with the target the DNA. Studying the thermodynamic and kinetic parameters of the base pair of RNA: DNA hybrids is very important to further understand biological function of RNA:DNA hybrids and to design genetic drugs. However, at present, the thermodynamic and kinetic parameters of the RNA:DNA hybrids are extremely scarce. Therefore, in this project, we will use statistical mechanics and transition state theory combined with all-atomic molecular dynamics methods to obtain the thermodynamic and kinetic parameters of hybrid base pairs, and further reveal the micro-mechanism of on-off dynamics. Furthermore, we will further investigate the effect of adjacent neighbor base pair and ions and analyze the physical mechanism. It would provide the basis for predicting the structural stability and kinetic behavior of different RNA:DNA hybrids. We will also study the effects of ssDNA on the RNA:DNA hybrids and R-Loop, which would be helpful to understand the relationship between RNA: DNA hybrid structure and disease from the atomic level, and provide some theoretical basis for the genetic drug design.