DNA G-quadruplex折叠热力学和动力学的多尺度模拟研究

DNA G-quadruplex是一种具有重要生理功能的结构，同时也具有研制抗癌药物的巨大价值。但是，G-quadruplex结构的形成过程，特别是金属离子调控的折叠热力学和动力学机制，目前依然没有原子层次的清晰图像。本项目将借助全原子和粗粒化分子动力学模拟，从多种尺度系统地研究这一问题。这是一项创新性的工作。具体内容包括：1）利用全原子分子动力学，结合凝聚态物理中先进的构象采样方法，计算自由能，分析金属离子调控的G-quadruplex折叠的热力学机制；2）优化粗粒化模型，研究金属离子调控的G-quadruplex折叠的动力学机制。探究DNA序列形成G-quadruplex的过程，分析影响其折叠的各种因素，不仅对我们了解DNA分子的动力学特性具有重要意义，也可以为设计抗癌药物提供新思路。同时，本项目将致力优化和发展分子动力学模拟方法，为研究生物大分子的折叠提供新的途径。

DNA G-quadruplexes are structures with important biofunctions. They are also attractive drug designing targets for treating cancer as their valuable property of anticancer. However, the atomistic folding process of DNA G-quadruplexes, especially the knowledge of the thermodynamics and kinetics mechanisms under the mediate of metal ions, is still unclear. Here, we will study the folding mechanism of DNA G-quadruplex using multiscale molecular dynamics method in this project. The strategy is like the following: 1) Studying the folding thermodynamics of DNA G-quadruplex with the mediate of metal ions with all atom molecular dynamics combining advanced sampling method. 2) Optimizing the coarse grained model and studying the folding kinetics of DNA G-quadruplex with the mediate of metal ions. The study of the folding mechanism of DNA G-quadruplexex, especially the knowledge of the factors affect the folding process, will help us to understand the dynamics of nucleic acids furtherly. It will also shed light on the designing drugs for treating cancer. Moreover, we will expand the usage of molecular dynamics in the field of molecular dynamics by optimizing the advanced sampling method and coarse grained method.