Theoretical Studies On The Radical Properties And Damage Mechanism Of Nucleic Acids

Nucleic acids are well-known to be the molecular carriers of hereditary information in living organisms, and play a very important role in life process. In addition, free radicals play a significant role in the oxidative damaging to DNA, amino acids, proteins, and membrane lipids. Accordingly they are deeply involved in many important chemical and biological processes such as aging and a number of human diseases including cancer, cardiovascular disease, and neurological dysfunctions. Therefore, To research the physico-chemical properties of nucleic acids and corresponding radicals, and to research the relations between DNA lesion induced by endogenous free radicals and diseases (cancer and so on) are one of the main directions in the area of modern biophysical organic chemistry, biochemical as well as biomedical. However for the reason of limitation of experimental conditions and lack of experimental methods, it is very necessary and important to research nucleic acids by means of quantum chemistry theoretical method.This dissertation focuses on nucleic acids and corresponding radicals, and deeply study physico-chemical properties of ribonucleosides and deoxyribonuclcosides with their radicals, and lesion mechanism. The research topics are as follows.We develop a new composite ab initio method ONIOM-G3B3 which is evaluated against 179 experimental C-H, O-H and N-H bond dissociation enthalpies of diverse organic molecules to verify their performance. It is found that the ONIOM-G3B3 can be used to reliably predict the bond dissociation enthalpies of diverse organic compounds, and the accuracy is about 1.4 kcal/mol. Using this method, it is feasible to accurately predict the bond strength of various sizable molecules ranging from nanosize molecular devices to biologically significant compounds.We optimize deoxyribonucleosides starting from a conformation identical to the B form of DNA and ribonucleosides starting from a conformation identical to the A RNA form which are considered the most important one for biological systems. From these conformations, the advanced theoretical reasearch can go on. In addational, using the ONIOM-G3B3 method, a full scale of C-H and N-H BDEs were obtained for the first time for ribonucleosides and deoxyribonucleosides with an estimated error bar of±1.4 kcal/mol. Nucleosides represent one of the most important groups of compounds in science. A full scale of reliable bond dissociation enthalpies for nucleosides is of fundamental importance.We also optimize deoxyribonucleoside 3',5'-bisphosphates (in both neutral and negative patterns) starting from a conformation identical to the B form of DNA and ribonucleoside 3',5'-bisphosphates (in both neutral and negative patterns) starting from a conformation identical to the A RNA form, which are considered the most important one for biological systems. Chosing nucleoside 3',5'-bisphosphates as model compounds for DNA and RNA, we fully study the effects of both the 3',5' phosphorylation group and water on relative stabilities of ribonucleosides and deoxyribonucleosides sugar radicals. It was found that the anionic phosphate group (-OPO₃H^-) was a better radical stabilization group than the OH group, whereas the neutral phosphate group (-OPO3H2) was a significantly worse radical stabilization group than OH. Strikingly, the bond dissociation free energy of C₂'-H in ribonucleotides was dramatically lower than that of all the other C-H bonds by 5-6 kcal/mol regardless of the phosphorylation state and the charge carried by the phosphate group.We develop a new method cosmors//cpcm//uahf to accurately predict the standard redox potentials of intermediates in the lesion process of DNA and RNA in aqueous solutions. Using this method, we predict the standard redox potentials of almost all the intermediates. From these reusts, the advanced study on the mechanism of DNA and RNA lesion process occurred by electron- transfer reaction in bio-systems.Radical-scavenging antioxidants play a pivotal role in the inhibition of oxidative damage by the free radicals. Using the newly-developed ONIOM-G3B3 method, the bond dissociation enthalpies (BDEs) of ten classes of popular antioxidants were systematically studied. These antioxidants included coenzyme Q, flavonoids, curcumins, olives, indolinonic hydroxylamines, phenothiazines, edaravones, commercial antioxidants used as food additives, vitamin E and catechins. The structure-activity relationships for various classes of antioxidants and radical scavenging mechanism are studied, and solve some controversies from the earlier literatures, which would be useful for us to predict the structure of new and effective antioxidants and provide help in the design of novel antioxidants with improved activities.Theoretical quantum chemical study is reliable because of its first principle. Theoretical studies can resolve the problems which are difficult or inaccurate in experiments. The research result of this dissertation provides valuable and fundamental information to the development of free radical biology and gene therapy.