液相DNA及其阴离子基态破损的QM/MM模拟方法发展和机理研究

放疗产生的电子可能会损伤活体细胞内DNA分子。一个重要损伤途径是液相DNA及其阴离子基态的破损。这个破损主要由碱基与糖环之间的化学键和糖环与磷酸之间的磷酸酯键的断裂及碱基上氢原子的摘除等反应所造成。本项目拟采用QM/MM方法研究液相DNA及其阴离子基态破损的机理。计划在最近提出的高效的DOBR微迭代优化算法基础上，进一步改进这个算法，提高局域结构优化效率，发展高效的QM/MM自由能计算方法。采用新发展的方法，计算液相中脱氧核苷、脱氧核苷酸和DNA及它们阴离子基态键的解离自由能，计算液相DNA及其阴离子基态碱基氢原子摘除自由能路径。探索可能导致液相DNA及其阴离子基态损伤的反应路径，考察环境水、碱基、糖环、磷酸等因素对反应路径的影响。

The electrons produced by radiotherapy possibly damage the DNA molecules in the living cells. One important pathway is the chain break on the ground state of DNA and its anion solvated in water, which could be caused by the excision of the base hydrogen and the bond cleavages of base-sugar, sugar-phosphate and hydrogen bond. In the project, we would apply the QM/MM computational method to investigate the mechanism of the damages for the ground-state DNA molecule and its anion solvated in water. The high-efficiency DOBR microiterative optimization of the new suggestion would be improved to further reduce the computational cost. Moreover, the efficient method to compute the QM/MM free-energy reaction path would be developed to calculate the free energy of the bond cleavages for the deoxynucleosides, deoxynucleotides, DNA, and their anions solvated in water and the excisions of the base hydrogen of DNA and its anion in water. According to the computational results, we explore the possible reaction path of the damages for ground-state DNA and its anion in water, and examine the effect of water, bases, sugar, and phosphate etc. on the damaged reaction path.