Theoretical Studies On Deprotonation Of Guanine Radical Cation Mediated By Water Clusters

Proton transfer is one of the basic processes of DNA involved chemical reactions.Because it is closely related to the charge transfer and oxidative damages in DNA,the microscopic mechanism of proton transfer of DNA molecules becomes a popular scientific topic.Among the nuclear acid bases,guanine（G）has the lowest ionization potential and aqueous oxidation potential and is easily oxidized to guanine free radical cation(G^·+).In order to explore the microscopic mechanism of G^·+deprotonation and proton transfer,this thesis uses QM method to study the effect of water molecules on the process of G^·+deprotonation in gas phase;QM/ABEEM（MM）method is developed to simulate and explore the microscopic mechanism of deprotonation and proton transfer of G^·+.The main contents are as follows:1.The deprotonation reaction of G^·+is studied at the M06-2X/6-31++G（d,p）level.The deprotonation reaction of G^·+is simulated in the model systems containing 3/4/5/7/9 water molecules,respectively,to obtain the transition states of the above five systems are found and the intrinsic reaction coordinates（IRC）.It is found that the participation of water molecules plays a key role in the proton release and transfer process of G^·+.When three water molecules are added near the G^·+deprotonation site,reasonable proton transfer cannot occur;the fourth water molecule will play an important role in promoting the G^·+deprotonation,and this water molecule can help the proton to locate in the first hydration layer of G^·+.It is also shown that the proton transfer after deprotonation of G^·+is directional.Extra more water molecules in the second hydration layer are ineffective to the proton transfer path,with quite small fluctuations of charge distributions and activation energies.Therefore,the model system involving four water molecules（referred to as 4H₂O system）is used as a reference for further simulating the proton transfer process of G^·+in aqueous solution.2.According to the QM results,the QM/ABEEM（MM）multiscale model is developed to deeply explore the microscopic mechanism of deprotonation and proton transfer of G^·+in aqueous solution.The QM IRC of the 4H₂O system was divided into three reaction regions:reactant,transition state,and product.The corresponding charge conservation conditions were set accordingly.,determining the valence electronegativity piecewise function by delineation,the ABEEM/MM parameters of each region are fitted and optimized.The obtained charge distributions of each region is in good agreement with the QM results,and the linear correlation coefficients between them are all above 0.97.27 structures on the IRC are selected to perform 500 ps QM/ABEEM（MM）molecular dynamics simulations in aqueous solution,and the activation free energy of the G^·+proton transfer process by the free energy perturbation method is 16.3 k J/mol,which is consistent well with the experimental results（15.1±1.5 k J/mol）.The work provides a consideration for further study of the DNA proton transfer process and the related mechanism of DNA oxidative damage.