Dna Base Isomerization And Alkylation Damage In Theoretical Research

The DNA damage means all kinds of the abnormal changes of DNA molecular structure. Including,the breakage and crosslinkage of double helical structure of DNA chain, isomerization,deamination alkylation of DNA base.Most of DNA damages can be repaired by the repair system in biology body,which is the foundation to maintain the genetic stability.The number of un-repaired DNA damages is thimbleful,but these un-repaired damages maybe produce very important influence on organism.In the replication process,DNA damage can lead to gene mutation and bring forth senescence,tumor and other diseases related to gene. Some DNA damages may be transmitted to filial generation,which is called gene mutation in genetics.Gene mutation can do organism a lot of harm,for example,it can induce cancer.On the other hand,it may endow the cell new function,and finally result in biological evolution. Moreover,the mutation induced artificially is the important approach to improve or create species,prevent or cure cancer and other diseases related to gene.Thus the research of DNA damage mechanism is a very important subject in life science.In this dissertation,we studied the isomerization of pyrimidine and purine base and methylating of base pair with density functional theory(DFT)calculations.Our purposes are to shed light on the mechanistic details of isomerization and methylation of DNA damage.The research of occurring and developing mechanism of DNA damage is the basis of utilizing advantageous damage and inhibiting disadvantageous damages.So it is very important research topic in biology and chemistry.The valuable results in this dissertation can be summarized as follows:The mechanism of DNA damage caused by the isomerization of pyrimidine base has been systematically studied by performing density functional theory calculations at the B3LYP/6-311+G(d,p)level.It is shown that the isomerizations of pyrimidine base can be classified into two types.The first is the hydrogen transfer between atoms,whose transition state includes a four-member ring.The second is the bond N-H rotation about the double bond N=C,and the plane CNH is perpendicular to the molecular plane in its transition state.The hydrogen transfer has higher reaction potential barrier,larger tunnel effect,and smaller equilibrium constant and rate constant than that of the N-H rotation.When the effects of hydration are considered in the framework of the polarizable continuum model,the two types of isomerizations will all have larger reaction barrier,larger tunnel effect and smaller rate of constant.The isomerizations leading directly to DNA damage are endothermic reaction and thermodynamic nonspontaneous processes.The DNA damage rate caused by the self-isomerization of cytosine and thymine is very slow.The probability of DNA damage caused by the cytosine isomerization is larger than that by the thymine.The mechanism of DNA damage caused by the isomerization of purine base is studied with density functional theory calculations at the B3LYP/6-311+G(d,p)level.The transition states of all the isomerizations are obtained,and the intrinsic reaction coordinate(IRC) analyses are performed to identify these transition states further.The isomerizations of purine bases can be classified into two types.The first is the hydrogen transfer between atoms,whose transition state includes a four-member ring.The second is the bond N-H rotation about the double bond N=C,and the plane CNH is perpendicular to the molecular plane in its transition state.The hydrogen transfer has higher reaction potential barrier,larger tunnel effect,and smaller equilibrium constant and rate constant than that of the N-H rotation.Effects of the hydration are considered in the framework of the polarizable continuum model(PCM)in SCRF method at the B3LYP/6-311+G(d,p)level.The isomerizations which result in the configuration changes of purine base and bring directly the DNA damage are endothermic and thermodynamic non-spontaneous process.The probability of DNA damage caused by the guanine isomerization is larger than that by adenine.Methylation of Watson-Crick adenine-thymine(A-T)and guanine-cytosine(G-C)base pair have been investigated by density functional theory calculations at the B3LYP/6-3 l+G(d,p) level.Calculations show that the 11 methyl isomers may be divided into two groups.(1)The methyl adds to an atom that is directly related to the hydrogen bonds of the base pair.(2)The methyl atom adds to an atom that is away from the hydrogen bonds of the base pair.In the fist group,N7-meG-C,N3-meG-C,N3-meA-T and N7-meA-T maintaining the planar structure of base pair have less influence on base pair damage.In the second group,N1-meA-T,N3′-me T-A,O4′-me T-A,O2′-me T-A,N3′-meC-G and O2′-meC-G which changes base pairing sequence,may cause a major lesion of DNA.Except O2′-meC-G,the base pairing energy of other isomers are increase because the methyl is donor group.Isomers of methylating guanine are more stable than the isomer of methylating cytosine.Isomers of methylating thymine are more stable than isomer of methylating adenine.There is no direct relationship between the charge distribution and the stabilization energy.Charge transfer exists in base pair,when the methyl adds to the cytosine, charge transfer less charge than methyl adds to the guanine.In methylating A-T base pair isomers,when the methyl adds to atom of O2,O4,N3 in thymine,the atom of H3′transfer to N1 in adenine,so the increase of charge all exit in adenine.In summary,the research of the isomerization and methylation of DNA elucidate the isomerization mechanism and the influences of methylating base pair on DNA damage.It is. important to understand deeply the nature of DNA damage process to explore further the conditions of influencing DNA damage and further to control and utilize the process of DNA damage.