Study On Related Problems Of Purine Damage And Functionalization

Guanine and adenine are two important components of DNA bases.During the vital movement,purine is prone to be modified by physical and chemical factors.Such DNA damages including rupture of DNA,formation of exocyclic purine adducts or interaction with metal cation would alter the stability,the acid-base behavior and the pairing ability of the base or the base pair,and thus influence the stability of DNA double helix and the accurate expression of genetic information finally.Recently,with the development of modern biology and molecular biotechnology,the study on the functionalization of DNA with freewill cut or chemical modification by various groups has achieved increasing attention.This paper explored the related problems on purine damage and its functionalization,in which chapters 2～4 mainly discussed the influence of purine damage on properties of purine(base pair);chapters 5 and 6 mainly explored the application of modified purine in ionic liquid.We found some interesting phenomena and obtained some valuable results.The main results are as follows:Mutagenie Research of trans-4-hydroxyl-2-nonenal:The reaction mechanism of guanine with trans-4-hydroxyl-2-nonenal(4-HNE)and the mutagenic mechanism induced by adducts have been predicted at a molecular level from the energy point of view. 4-HNE directly reacts with guanine via three steps,yielding eventually four main diastereoisomers:trans-4-HNE-dG adducts.A concerted six-atom-centered transition state is proposed for the first step,while the last two steps are involved in four-member-ring transition states.The third step is the rate-determining step.The studies of base pairing properties of trans-4-HNE-dG adducts with A,T,C,A^*,and T^* together with the relationship between the mutation and structure of trans-4-HNE-dG indicate that syn-and anti-conformations of trans-4-HNE-dG around the glycosidic bond are favorable for pairing with A^* and T^*,respectively,in the parental generation.As a result,the GC to CG or GC to TA mutation may be generated from the syn-4-HNE-dGA^* during replication.Nevertheless,anti-4-HNE-dGT^* creates GC to TA mutation or nonmutagenesis.Moreover,syn-4-HNE-dGA^* has a slightly higher probability to be generated than anti-4-HNE-dGT^* in the parental generation;therefore,the GC to TA transversion is predominant among the mutations.Our mutational results have interpreted well a part of the discrete experimental observations,but the mutagenic process itself has not previously been characterized,through either computation or experiment.Influence of methylation of Purine on properties of GC and AT base pairs: The pairing strength,proton properties associated with proton transfer and deprotonation ability as well as relevant structural perturbations of 7,9-dimethylated GC([dMGC]⁺)and 7,9-dimethylated AT([dMAT]⁺)base pairs have been investigated.Energies related to proton transfer and deprotonation have also been predicted.It is found that the guanine/adenine N7 methylation improves the stability of GC/AT base pair.The proton transfer between the guanine N1 and the cytosine N3 is observed in[dMGC]⁺ with an out-of-plane transition state.However,no proton-transfer reaction occurs for[dMAT]⁺ system.For the deprotonation of[dMGC]⁺ and[dMAT]⁺,guanine C8 and N1 and adenine C8 are the most favorable sites.Deprotonation from N1 site of cytosine and thymine generates the most stable deprotonated base pairs,and the dissociation energies surprisingly amount to～100.00 and～65.49 kcal/mol,respectively,much higher than those of their corresponding neutral base pairs.However,deprotonation from the other sites of pyrimidine except N1 site exhibits the most significant structural changes and gives the most interesting deprotonated base pairs.This process accompanies by a barrier-free proton transfer(BFPT)from guanine N1 to cytosine N3 and adenine N6 to thymine N3 or O4 site.In this way,two rare tautomers of cytosine(trans-C^* or cis-C^*)are easily generated by removing a proton from N4 site of cytosine in[dMGC]⁺.In addition,the reason for BFPT from guanine N1 to cytosine N3 has been explored.Influence of copper(â… )and copper(â…¡)on gas-phase acidity of adenine: Gas-phase deprotonation of multiple sites in Cu^+/2+-adenine complexes have been investigated theoretically for the first time.To compare,the acidities of adenine(A)and adenine radical cation(A^·+)have also been included.The result indicates that the acidities of C-H and N-H groups in Cu⁺-adenine and Cu²⁺-adenine are significantly enhanced relative to the neutral adenine.The acidic order for a given site on adenine and adenine derivatives is as follows:Cu²⁺-adenine＞A^·+＞Cu⁺-adenine＞A.For Cu⁺-adenine and Cu²⁺-adenine,N3-coordination exhibits N9-H acid,while N1-and N7-coordination exhibits N6-H^a and N6-H^b acid,respectively.Additionally,it is found that C2-H group is surprisingly acidic in the coordination complexes,especially in 1a, 3a/b and 7b;it becomes the second acidic group.Analyses of the electronic properties interpret the highest acidity of Cu²⁺-adenine among the adenine derivatives studied.Also, electrostatic potential calculations of[A(-H⁺)]^- and[A(-H⁺)]^·indicate that the removal of H^a or H^b from the amino group favors the bidentate coordination,which provides a dative bond from the deprotonated N(N6)and the original coordination ligand to copper ion besides the electrostatic interaction between them and thereby stabilizes the[A(-H⁺)]^- / [A(-H⁺)]^·.NBO analysis confirms the electrostatic potential result.The structures and characters of N7,N9-dimethylguaninium chloride ion pair:The last two parts mainly investigate the potential application of the chemically modified guanine in ionic liquid.The original idea to design this kind of ionic liquid is based on the evidence that the cation is a hereditary material and thus to compare with the conventional ionic liquid,this kind of ionic liquid is biodegradable and more favorable for biological reaction.The structures,IR spectra and electronic properties of the N7,N9-dimethylguaninium chloride have been studied.The interaction of one cation with one to four Cl anions and one Cl anion with two cations were investigated.Fifteen stable conformers are obtained.It is found that there are four acidic regions in the vicinity of the guaninium cations.In these regions,the cation could H-bond with one to three Cl anions but no more than three nearest anions.One Cl anion could H-bond with two cations.Additionally,evidence of Cl...Ï€interaction between the anion and cation is observed.Among these structures,one cation interaction with two anions and two cations interaction with one anion have the larger interaction energies than the other series. NBO analyses and MOs reveal that the charge transfer from anion(s)to the cation(s) occurs mainly through either the Cl^lp→σ_C-H^*,Cl^lp→σ_N-H^* or Cl^lp→π_C8-N7^* interaction. The interaction between Cl andσ_(C/N-H)^* orÏ€_C-N^* produces a small bond order.This indicates that Cl...H(Cl...Ï€)interaction exhibits a weak covalent character and suggests a strong ionic H-bond(Cl...Ï€bond).What's more,formation of Cl...H/Cl...Ï€bond decreases the bond order of the associated C/N-H bond or C⁸-N⁷ bond.In addition, examination of vibrational spectrum of each conformer explains the origin of H-bonding character.Influence of various anions on properties of ionic pairs based on dimethylguaninium:This part systemically investigated the influence of various anions (including fluoride,bromide and tetrafluoroborate)on the structures and properties of ion pairs based on N7,N9-dimethylguaninium.The interaction of one to three F(Br or BF₄) anion(s)with one N7,N9-dimethylguaninium and the related structural and electronic properties have been explored.The calculations show that the cation interactions with one to three anion(s)give 31 stable structures.Among these structures,the cation interactions with two anions,especially in the regions S1(N1-H or both N1-H and N2-Ha) and S3(C8-H),are the most favorable,while the interactions with one anion are the least favorable.Moreover,with the increase of the anionic radius of fluoride(F),bromide(Br) and tetrafluoroborate(BF₄),the interaction energies are decreased.NBO analyses reveal that the charge transfer from Br or BF₄ anion(s)to the cation occurs mainly through X^lp→σ_C/N-H^* or/and X^lp→π_C8-N7^* interaction(s).These interactions between X andσ_C/N-H^* or/andÏ€_C-N^* produce a small bond order(X=Br/BF₄),indicating a weak covalent character and thus suggesting a strong ionic H-bond(X...Ï€bond).However,the charge transfer from F anion(s)to the cation could also occur through the formation of F-H/C covalent bond besides F^lp→σ_C/N-H^* or/and F^lp→π_C8-N7^* interaction(s).On the other hand, comparison of the bond order of[dMG]·mF,[dMG]·mBr and[dMG]·mBF₄ series reveals that,with the increase of the anionic radius,the desired ionic bond is more favorable than the covalent form.Strong covalent character between F anion(s)and the cation may suggest that N7,N9-dimethylguaninium fluoride is not suitable to be selected as an ionic liquid,since F is prone to covalently bond with the cation C8 or the hydrogen attached to it.