Theoretical Study On The Interactions Of Metal Ions With DNA Base Pairs

As is well-known, genetic information is stored and duplicated in nucleic acids which can thus be considered as one of the most important molecules in our life. Metal cations have significant influence on the structure, dynamics and function of nucleic acids. The interaction between metal ions or metal ion adducts with the nucleic acid bases is the base of discovery of antitumor drugs, make of spectrum probes and reaction probes, and development of nanometer scale DNA-based device technology. Thus, it is fundamentally important to understand the chemical nature of interactions between metal cations with nucleic acid bases.In the present paper, we investigated the interaction between metal cations with DNA bases and DNA base pairs using the high-level quantum chemical computation methods. The main results are as follows:1. The different affinity of the studied metal cations (Mg²⁺, Zn²⁺, Mn²⁺, and Ni²⁺) for the N7 position of guanine in GC WC or GG rH base pair has been quantitatively characterized using density functional theory (DFT), highly correlated treatments, AIM analysis, and NBO analysis to explore the origin of difference of the melting temperature of DNA when presenting different metal cations. From comparing the difference of the molecular structures, topological analysis, NBO analysis, the total interaction energies, and the hydrogen-bond interactions in base pairs between isolated nucleobases and metalated nucleobases; the energy differences of formation of the ion-pair between isolated nucleobases and metalated nucleobases; the difference of energy penalty for changing the coordination number of different metal cations–GC complexes with one or two water molecules in the second shell, we propose that the energy penalty for changing the coordination number of metal cation-necleobases complex seems to be dominant to explain the difference of the melting temperature of DNA when presenting different metal cations.2. We have numerically compared the changes of the hydrogen bonds in the AT base pair upon the hydrated metal cations(Na⁺, Mg²⁺, and Zn²⁺)binding the adenine-N3 of AT or the adenine-N7 of AT base pair, using the electron density topological analysis and NBO analysis at B3LYP/6-31++G(d,p) level of theory, to discuss the differences of the hydrogen bonds when presenting the hydrated metal cations binding to major grooves or minor grooves of DNA. In comparison with the hydrogen bonds in the isolated AT case pair, the changes of the hydrogen bonds when presenting the hydrated metal cations at A-N3 position are different from those when presenting the hydrated metal cations at A-N7 position. Due to the much stronger hydrogen bond interaction when binding the hydrated metal cations to the N3 of adenine in AT, it is possible that the N3 position of adenine in minor groove of DNA can also be a potential target for platinum-based chemotherapy.3. We have quantified the binding energies between cations and G tetrad in G4-M^Z+-G4 (inter) complexes (M^Z+=Li⁺, Na⁺, K⁺, Rb+, Cs+, Mg2+, Ca2+, Sr2+, and Ba2+) using DFT, highly correlated treatments, AIM analysis, and NBO analysis, to discuss the effect when presenting metal ions both in stabilization and destabilization of G-tetrad complexes and the origin of metal ions selectivity. On the basis of theoretical results, we found the stability order of the metal cations in the G4-M⁺-G4 complexes obtained from supermolecule calculation method, whether it is corrected by the hydration energy or not, obviously conflicts with the experimental observations. According the topological analysis and relaxation energy sequence of G4-M⁺-G4 complexes (M⁺=Li⁺, Na⁺, and K⁺), we proposed that the ion selectivity in the G tetraplexes is still dominated by the optimal fit of the cations not by relative energies of hydration.4. To gain insight into the effect of the electron density redistribution induced upon cation binding on the interaction between bases, we have compared the molecular electrostatic potential (ESP) computed by B3LYP/6-31++G(d,p) between GC Watson-Crick, GG r-Hoogsteen, and AT Watson-Crick base pairs with the counterpart metalated base pairs. According the ESP, there are many negative ESP sites around the isolated base pair where tend to bind with metal cations. After the hydrated metal cations binding with the N7 position of guanine in GC WC or GG rH base pair and the adenine-N7 of AT base pair, there are significant changes in ESP that the negative ESP charges are disappeared whereas the positive ESP charges are increased. It is worth noting that the changes of ESP in base pairing with hydrated metal cations may affect subtle environment of base pair and influence the structure, dynamics and function of nucleic acids.5. The influence of the local environment (water, histidine, or glutamate anion) on the properties of tyrosine and the process of 3-nitrotyrosine formation with the presence of glutamate residue have been investigated in detail at the B3LYP/6- 31++G(d,p) theory level. The results show that the presence of glutamate anion within a few angstroms from the tyrosine residue (a) may help the tyrosine more likely to ionize and more easily to form radical by acting as a proton acceptor; (b) may stabilize the intermolecular complex M1 and direct the nitro reagent to the two equivalent ortho carbons of the aromatic ring of tyrosine residues mainly by the N…O interaction whose geometry is found to be vertical with the plane of nitro due to the electrostatic interaction between N atom of·NO₂ and O atom of glutamate anion; (c) may assist to form the more stable complex M3 through the concerted double proton transfer, in which the glutamate residue acts as a proton switch to catalyze the proton transfer.