Studies On The Properties And Functional Mechanisms Of Guanine And Its Derivatives Associated With The DNA

Guanine (G) is one of the primary components of the DNA, with the lowest oxidation potential among four DNA bases, so the oxidation in DNA damage is predicted to be produced at this site. They have several active sites, such as N and O, which incarnate the effects from the outer factors on its structures and properties. Thus, in the present dissertation, the effects of various outer factors, such as metal ions, oxidation, deprotonation, proton transfer etc. on the hydrogen bond character and the ability of the paring of the guanine and GC base pair have been investigated in detail. On the basis of the prevenient studies, the influencing factors of the fidelity synthesis of DNA and the formation of the mispairs have been investigated, then the aim to reveal the secret of life can be carry out step by step. Some significant progresses have been made, which can be described as follows.1. The cognition on the dissociation energy and H-bond character of G-C cation and Li-GC cation is the basis to understand the biological function. The one electron oxidation and the coupling of Li⁺ to guanine-cytosine base pair can strengthen the interaction between guanine and cytosine. The interaction of the cation Li⁺ with guanine is attractive and is attributed to the polarization of the H-bonds between G-C that enhances G-C interaction. The cooperativity of the three H-bonds in the GC and Li-GC cations are different from that in the neutral GC base pair. The proton transfer process of between N₁ of the guanine and N₃ of the cytosine can occur in the GC cation and the Li-GC cation. The geometries of the transition state are out-of-plane, especially for the transition state of the Li-GC cation. The analysis of the activation energy for the proton transfer process shows that the GC⁺ before and after proton transfer can exist simultaneously in the gas phase, but for the Li-GC⁺ system, the Li-GC⁺ without proton transfer is the dominating species in the gas phase.2. On the basis of the results of the GC cation, the effect of the addition of the sugar moiety on the character of the GC base pair has been investigated. The ionization of an electron from dGdC results in remarkable changes to the three hydrogen bonding distances, the O…H4-N4 distance increased by 0.160 A and the N1-H1…N3 distance and the N2-H2…O2 distance decreasing by 0.116 A and 1.234 A, respectively. The ionization potential of the dGdC pair was studied to reveal the correct trends of adiabatic ionization potential (AIP) under the influence of the additional components to the individual bases. The consequence of positive charge in terms of structural variations, energetic changes, and charge distribution were explored. The AIP of dGdC is predicted to be positive (6.48 eV), and it exhibits a substantial increase compared with those of the corresponding bases G and C and the nucleic acid base pair GC. The effects of pairing and the addition of the sugar moiety on the AIP are well described as the summation of the individual influences. The influence of the pairing on the G is comparable to that of the addition of 2-deoxyribose. The singlet charge is mainly located on the deoxyriboguanosine moiety in the cationic dGdC pair. The negative vertical electron attachment energy (-5.98 eV) for dGdC⁺ suggests the cationic state is unstable with respect to electron attachment vertically. A large vertical ionization potential (VIP 7.05 eV) has been determined for the neutral dGdC nucleoside pair. The proton-transfer process between N1 of the guanine and N3 of the cytosine can occur in the GC cation and dGdC cation, and this process becomes easier when the sugar moiety linked on the base pair. Therefore, one may expect that the cationic dGdC nucleoside pair before and after proton transfer should be exist simultaneously.3. The variation of N1-H proton release energy of G-M (M=Li, Na) cation have been investigated. There are three modes (NO mode, N mode and O mode) when the hydrated-M⁺ bonds to guanine. The bonding energy of the hydrated M⁺ to the guanine reduces following the increase of the number of the water molecule. The proton release energies of the G-M⁺ complexes are calculated at the condition of the different numbers of the water molecules and the different modes of the water molecules bonded on the G-M⁺. The results show that the difference of the proton release energy on three modes is very small, and the proton release energies of the Na⁺ complexes are slightly larger than that of the Li⁺ complexes. The effect of the water molecules bonded on the M⁺ cation on the N1-H proton release is very small, but the effect is very large when the water molecules bond on the N1-H proton and the proton release as the hydrated proton. The vibrational frequency analysis shows that the changes of the vibrational frequency are consistent with the changes of the geometry and the changes of the N1-H proton release energy. The N1-H proton release (N1-H proton release energy: 45-60 kcal/mol) of the guanine can occur easily at the condition of the biology system.4. The effect of the ionization of the guanine and the deprotonation of the guanine cation on the formations of base pairs and on the hole transfer in DNA was explored. The base pairing with neutral DNA base lowers the adiabatic ionization potential of guanine, while the base pairing with protonated DNA base heightens the ionization potential of guanine. The lower of the adiabatic ionization potential of guanine in Watson-Crick mode base pairs has a slight effect on the hole transfer, but the structural changes resulted from the DNA base mispair may break theÏ€-stack in DNA helix, thus make against the hole transfer. The mispairs GA-1 and GA-2 increase the probability of the hole transfer from one strand to other strand. The protonated A, T, C and neutral G pairing with guanine through Hoogsteen mode may significantly affect on the hole transfer, but the mechanisms are different from each other. When the protonated A, T or C base pairs with guanine through Hoogsteen mode, the ionization potential of guanine has been increased and thus the hole transfer may be stopped. While the neutral guanine pairs with guanine through Hoogsteen mode, the ionization potential of guanine has been decreased significantly and thus the hole can spontaneously transfer to the third strand and can be trapped by the Hoogsteen base pair GG when the hole transfer along the DNA helix. In the view of the energy, the one electron ionization of guanine can not result in the Watson-Crick mispair of DNA base pair, but the deprotonation from the guanine cation is in favor of the combination of the G(-H) and guanine. In the Hoogsteen base pairs. the one electron ionization of guanine affects slightly on the interaction mode, but it may result in the dissociation of the Hoogsteen base pair if the DNA bases pairing with guanine are the protonated A, T and C. Dehydrogen from guanine affects slightly on the hydrogen bonding energy of the Hoogsteen base pairs.5. The mechanism of the fidelity synthesis of DNA associated with the process of the dGTP combination to the DNA template was explored. The excluding of water molecules from the hydrated DNA bases can amplify the energy difference between the correct and incorrect base pairs, but the effect of the water molecules on the Gibbs free energy of formation is dependent on the binding sites for the water molecules. The water detachment from the incoming dNTP is not the only factor but the first step for the successful replication of DNA. The second step is the selection of the DNA polymerase on the DNA base pair through the comparison between the correct DNA base and the incorrect DNA base. The bonding of the Arg668 with the incoming dNTP can enlarge the Gibbs free energies of formation of the base pairs, especially the correct base pairs, thus increase the driving force of the DNA formation. When the DNA base of the primer terminus is correct, the extension of the guanine and the adenine is quicker than that of the cytosine and the thymine because of the hydrogen bonding fork formation of Arg668 with the minor groove of the primer terminus and the ring oxygen of the deoxyribose moiety of the incoming dNTP. Due to the geometry differences of the incorrect base pairs with the correct base pairs, the effect from the DNA polymerase is smaller on the incorrect base pair than on the correct base pair, and the extension of a mispair is slower than that of a correct base pair. This decreases the extension rate of the base pair, and thus allows a proofreading exonuclease activity to excise the incorrect base pair. Arg668 can not prevent the extension of G/T mispair as well as the G/C correct base pair and G/A, G/G mispairs. This may be attributed to the small geometry difference between the G/T base pair and the correct A/T base pair.