Development Of ABEEM Polarizable Force Field Combined With QM Method To Study The Reaction Mechanism Of Damaged Guanine By Repair Enzymes

DNA damage will lead to aging,cancer even death.The 2015 Nobel Prize in Chemistry has experimentally revealed that repair enzymes in the human body have a repairing effect on DNA damage.Repair mechanism is the fundamental to maintaining life and health.In order to treat diseases related to DNA damage,it is necessary to clarify the enzyme-catalyzed reaction mechanism of the enzyme to remove the damaged base.The experiment could not get the relevant details.Studying biological system chemical reaction by QM/MM method is a research hotspot in this field.This work combined quantum chemical(QM)and ABEEM fluctuating charge polarizable force field,it is QM/MM(ABEEM)method,which is applied to study the catalytic reaction mechanism of guanine and damaged guanine.The specific research results are as follows:1.Repair enzymes react with guanine and damaged guanine by quantum chemistryTake nucleoside,amino acid residue(Asp)and water as model molecule.The transition states of the gas phase and the liquid phase(PCM model)were found using quantum chemistry methods,and were discussed and analyzed.Those results were taken as standand to develop QM/MM(ABEEM)model.The activation energy obtained by the PCM method is different from that in gas phase,and compared with the experimental value have a large difference.It is essential to simulate the real aqueous environment in vivo,so the mechanism of repairing enzymes to remove guanine and damage guanine is analyzed by QM/MM with explicit solvent molecules model to predict the solution effect.2.Developing QM/MM(ABEEM)combined with free energy perturbation method to explore the mechanism that of guanine removal by repair enzymesThe key point of this chapter is to find the transition state by QM/MM(ABEEM)combined with explicit solvent model,and to determine the parameters of the 100 structures on the reaction path by the distance function.ABEEM model was used to describe the organism environment,i.e.MM region.By comparing the structure of the reaction path obtained by QM and QM/MM(ABEEM)methods,we could see that the optimized transition state under QM/MM(ABEEM)model was the most reasonable and closest to the real situation.The energy at each point on the reaction path was analyzed,indicating that the electrostatic interaction term played an important role in the calculation of total energy usingthe QM/MM(ABEEM)method.The activation free energy calculated by QM/MM(ABEEM)method is 31.84 kcal/mol,which is lower than that obtained in gas phase and PCM models.3.Applying QM/MM(ABEEM)combined with free energy perturbation method to explore the mechanism of 8-oxo-G removal by repair enzymesFor the oxidized base 8-oxo-G,the charge parameters of bonding and breaking atoms on the reaction path were redefined.The activation free energy calculated by QM/MM(ABEEM)and free energy perturbation method is close to the experimental value.Compared with normal base G,the activation free energy of 8-oxo-G under explicit solvent model is lower(17.45 kcal/mol),which confirms that the repair enzyme can remove OG to repair oxidative damage,instead of removing normal G.