DNA超螺旋的形成、结构多样性和构象转变研究

超螺旋结构是DNA的一种高级结构形态，在遗传信息存储、复制和转录，细胞生理功能调控，以及癌细胞发育中发挥着关键的作用。单分子操控等技术的发展，使我们可以直观地观察DNA超螺旋静态结构和形态，但是，人们对DNA超螺旋的形成、构象转变，尤其是DNA序列与超螺旋形态结构之间的关联，依然缺乏深入的了解。本项目将采用理论模拟，结合energy landscape计算方法和马尔科夫状态模型方法，(1) 研究DNA超螺旋结构形成动力学路径和热力学机制，(2) 探索超螺旋的结构多样性和构象转变机制，(3) 发展基于DNA序列的DNA超螺旋结构预测模型，(4) 探究DNA超螺旋结构的迁移和重组机制。本项目研究将加深我们对DNA超螺旋形成物理机制、动力学行为和构象转变机制的理解，为精确设计和调控DNA超螺旋结构提供理论指导，为主动介入和干预癌细胞致病基因表达提供可能性。

DNA rarely exists in a relaxed and canonical state, and supercoiling is a transition from the relaxed state of the DNA double helix to one that is more under- or over-wound. Recent biochemical studies suggest that supercoiling plays an important role in the regulation of gene expression in both prokaryotes and eukaryotes, and in the development of cancer cells. Although the advances in mechanical manipulations of single biological molecule provide significant insight into the structure of supercoiled DNA, however, much about the biophysics of DNA supercoiling remains unknown. In the present proposal, using molecular modeling combined with the energy landscape computational framework and the Markov State Model, we suggest to: (1) investigate the detailed biophysical process of DNA supercoiling, (2) study the structural diversity and transformations of supercoiled DNA, (3) develop an analytical model for the prediction of DNA supercoiled structure based on DNA sequence and the nearest-neighbor (NN) model, (4) investigate the mechanism and kinetics of diffusion and reorganization of supercoiled structures. The expected results and conclusions will deepen our understanding of the structural diversity, folding mechanism, and kinetics of supercoiled DNA loops, facilitate the fine-scale control of the three-dimensional control of DNA supercoiling, and would also contribute to the potential applications in the cancer control interventions through modulating the DNA supercoiling in cellular processes.