DFT Studies on the Copper(II) Complexes of DNA Bases

DNA 염기의 구리(II) 착물에 대한 DFT 연구

RESULTS AND DISCUSSION

In Fig. 1, the most significant geometrical parameters of stable Cu2+-DNA bases complexes obtained by B3LYP/6-31G(d,p) computations are reported. The copper(II) cation association energies of DNA bases are summarized in Table 1.

Fig. 1.B3LYP-optimized structures for Cu2+ complexes of AC) adenine, TC) thymine, GC) guanine, and CC) cytosine. Selected distances are in Å.

All optimized structures in Fig. 1 have Cs symmetry except C1 of the CC2.

On the other hand, the cupric cation association energies of DNA bases are calculated to be about 200~260kcal/mol as shown in Table 1. These energies are larger than that of Cu+ complexes (90~140 kcal/mol)14 and are similar to that of Zn2+ complexes (180~250 kcal/mol).13 This means that the association energy relates to charge of the metal ion.

As shown in Fig. 1, the five distinct complexes of Cu2+ with adenine have been found. The structure of AC5 in the five complexes was not located in Cu+ complex.14 The cupric cation association energies of these complexes are about 230 kcal/mol except N7 complex of about 225 kcal/mol as shown in Table 1.

Association of adenine with Cu2+ is accompanied by structural changes within the pyrimidine ring. When Cu2+ binds at the N1 and N6 atoms(AC1 in Fig. 1), the N1-C2 distance increases by 0.023Å compared to the parent base, whereas the C5-C6 bond length of 1.411Å is reduced to 1.373Å in the complex. The notable change in bond lengths is an increase of 0.103Å in the C6-N6 distance. The C5C6N6 angle also changes considerably, increasing by 8.7°. The two dihedral angles (∠N1C6N6H) of -10.0 and -170.1° by amino hydrogens in adenine change to 119.7 and -119.7° in N1-N6 complex, respectively. This is due to the repulsion between the Cu2+ and amino hydrogen on the N1 side of the C6-N6 bond. That is, the amino hydrogens rotate to reduce this repulsion. The N1-Cu2+ and N6-Cu2+ distances of this complex are calculated to be 1.893 and 1.969Å, respectively. When Cu2+ binds at N3 (AC2 in Fig. 1), the N1-C2 bond length decreases by 0.051Å and the C2-N3 distance increases by 0.077Å. The N3-Cu2+ distance is 1.801Å. All other bond distance and bond angle changes are small. For the bridging complex in which Cu2+ forms a five-membered ring (AC3 in Fig. 1), the N7-Cu2+ distance is 1.897Å and the N6-Cu2+ is 2.025Å. The C5C6N6 angle changes considerably, decreasing by 8.2°. This large change is associated with bridging nature of the complex caused by interaction of Cu2+ with the N6 and N7 atoms. The N1-Cu2+ distance in the N1 complex(AC4 in Fig. 1) is calculated to be 1.815Å and N7-Cu2+ distance in N7 complex(AC5 in Fig. 1) is calculated to be 1.800Å.

Table 1.aΔEc = ΔE + ΔZPE + BSSE

The two association sites for Cu2+ complex with thymine have been found, one at each carbonyl group, as shown in Fig. 1. These features are similar to Zn2+ complex.14 The association energies of these complexes are calculated to be -207.74 and -203.10 kcal/mol in the O2 and O4 complex, respectively. The O-Cu2+ distances are 1.771 and 1.792Å. In this complex, the notable change is an increase in the internal angle of the ring at carbon of the carbonyl binding site, and increase in the carbonyl C=O bond lengths. The N1C2N3 angle in the O2 complex increases by 3.3° and the N3C4C5 angle in the O4 complex increases by 6.2°. The C=O bond distances increase upon complexation by 0.033 and 0.085Å in the O2 and O4 complex, respectively.

The three distinct complexes of Cu2+ with guanine have been found as shown in Fig. 1. The most stable guanine complex is the bridging complex in which Cu2+ forms a five-membered ring, interacting with the O6 and N7 atoms. The cupric cation association energy of this complexes is -262.54 kcal/mol as shown in Table 1. The five-membered ring formation (GC2 in Fig. 1) is about 40 kcal/mol more stable than the four-membered ring formation (GC1 in the Fig. 1). This result shows that the five-membered ring formation is favored with respect to formation of four-membered ring because of the minor annular strain. This O6-N7 five-membered ring complex of Cu2+ with guanine is the strongest of the Cu2+ complexes with the DNA bases as seen in Table 1. This tendency is similar to that obtained for the Zn2+ complex.14 In five-membered ring complex, the C5C6O6 angle decreases notably by 13.3° in comparison with parent base. This large change is also associated with the bridging nature of complex. The O6-Cu2+ and N7-Cu2+ distances of this complex are calculated to be 1.863 and 1.915A, respectively. On the other hand, the two N-Cu2+ distances in four-membered ring complex are found to be 1.937 and 2.073A. And N-Cu2+ distance in N3 complex (GC3 in Fig. 1) is calculated to be 1.814A.

The two bridged formations have been found in the cytosine complex in which Cu2+ forms fourmembered ring with O2-N3 and N3-N4 as shown in Fig. 1. The O2-N3 bridging complex is more stable than N3-N4 complex. This result means that the carbonyl oxygen is preferred over the amino nitrogen. In the O2-N3 complex, notable changes occur in bond distances and angles from N1 to C4. The N1-C2 distance decreases by 0.095Å and N1C2O2 angle increases by 6.8° with complexation. These results lead to enhancement of the simultaneous interaction of Cu2+ with O2 and N3. Similarly, the N3C4N4 angle in the N3-N4 complex is reduced upon complexation to about 11.3°. In the O2-N3 complex, the O2-Cu2+ and N3-Cu2+ distances are 1.853 and 1.942Å, respectively. In this complex, the O-Cu2+ distance is longer than the corresponding ones in the thymine complexes. The association energy of this complex is -245.71 kcal/mol. On the other hand, the N-Cu2+ distances in N3-N4 complex are calculated to be 1.865 and 1.997Å.

In conclusion, there are five distinguishable Cu2+ complexes with adenine, two bridging complexes and the other three open structures at N1, N3 and N7, respectively. There are two Cu2+ complexes with thymine, one at each carbonyl group. The three distinct complexes of Cu2+ with guanine are found, two bridging guanine-Cu2+ complexes and an open structure at N3. For the cytosine-Cu2+ complex, there are two bridging complexes, one at the O2 and N3 atoms, and the other at the N3 and N4 atoms.

In this study, structures and energetic aspects of the complexes of copper(II) with DNA nucleobases were investigated at B3LYP/6-31G(d,p) density functional level. The association energy values suggest that the most stable of the Cu2+complexes with DNA bases are the bridging complexes with guanine and cytosine at the O and N atoms. This means that the coordination sites are the O and N atoms as the most suitable to receive the metal cations. The most favorable association energy values for each base suggest that the DNA bases reactivity order with Cu2+ is guanine > cytosine > adenine > thymine. This tendency of Cu2+ metal affinities is in agreement with the experimental results from kinetic method for the alkali metals (Li+, Na+, K+).8

The results obtained in this study are the first theoretical consideration that concerned the Cu2+ interactions with DNA bases. These gas-phase results can be used with caution as a guideline for both the binding sites and association energies for the condensed phase.