Quantum-chemicalab initioStudy on the Adenine-Difluorotoluene Complex - A Mimic for the Adenine-Thymine Base Pair

Abstract

Recent experiments have shown that difluorotoluene (F), a nonpolar isostere for thymine (T), codes efficiently and specifically for adenine (A) in DNA replication. F has almost the same shape as thymine but it is unable to form conventional hydrogen bonds with adenine. Therefore, it has been claimed that not hydrogen bonding but shape complementary may be important for the selection of the correct bases by DNA-replicating enzymes. In order to gain deeper insight into structure, charge distribution and energetics of the A-F and A-T base pairs we have performed quantum-chemical ab initio and density functional calculations at the HF, MP2 and B3LYP levels. The interaction energy of the A-F complex amounts to -3.8 kcal/mol (MP2) and is thus substantially smaller than typical ab initio interaction energies for Watson-Crick or non-canonical base pairs. The A-T and A-F complexes are planar and their overall geometries are similar (root-mean-square deviation: 0.4 A). The calculated donor acceptor atom distances in A-T are in good agreement with the experimental mean values obtained from an analysis of 21 high resolution DNA structures. However, A-F shows a base pair opening as compared to A-T. Even though the interaction energy in the A-F base pair is small, the distances for the N6-H...F and N1...H-C3 contacts are still below the sum of the van-der-Waals radii, which means that the interaction is not governed by van-der-Waals forces alone. If the experimental findings can be confirmed, then our results indicate that DNA polymerase is able to retain high fidelity with base pairs of much smaller interaction energies than found for the conventional Watson-Crick and non-canonical base pairs.

Density functional study of guanine and uracil quartets and of guanine quartet/metal ion complexes

“…We have investigated the H-bonded ATbase pair and the unusual adenine-difluorotoluene (AF) pair and found close a correspondence between B3LYP and single-point MP2 base pair interaction energies. 14 The distances between both bases in AT-pairs from B3LYP calculations are in better agreement with experimental AT-pair distances in DNA structures than the ones derived from HF calculations. When compared with a MP2(FC) optimized structure, B3LYP performed better than HF for the geometry of a water-mediated base pair.…”

Mimicking the Structure and Function of DNA: Insights into DNA Stability and Replication

“…Fourth, F shows no measurable selectivity in pairing with A, while thymine displays 3 ± 4 kcal mol À1 of selectivity in the same context. Fifth, although calculations suggest that there might be one weakened hydrogen bond between F and A in the gas phase, [52,54] there appears to be general agreement among most computational scientists that in water there will not be nearly enough favorable interaction to explain our results. [52±54, 122] Finally, hydrogen bonds are completely ruled out in cases such as the pair between F and Z, which is still processed relatively efficiently by the enzyme.…”

“…Ab initio calculations of the relative F ± A and T ± A pair stabilities also fall in this range, and so the pair is predicted to be quite weak. [52,54] In addition, it has been pointed out that screening of the electrostatic attractions by waters high dielectric constant would lead to a significant reduction in this attractive force. [53] Most of the theoretical studies have concluded that this weak noncovalent interaction between F and A is not sufficient to explain later results in DNA replication (see Section 5.3).…”

Replication of non-hydrogen bonded bases by DNA polymerases: A mechanism for steric matching

“…Critics of the hypothesis that hydrogen bonds are not absolutely required have suggested that the reason for the success of the F-A pair in replication is that F is, in fact, forming a reasonably strong hydrogen-bonded complex with adenine. 73 While we and others have argued that the data do not support this, 35,37,63,64 more data would certainly be useful in examining this question. For example, if hydrogen bonds are the cause of the high efficiency of insertion of dATP opposite F, then insertion of a nonhydrogen-bonding isostere of dATP opposite F is expected to occur with very poor efficiency.…”

“…62 More recent studies of difluorotoluene itself suggest that the fluorine can form a single weakened hydrogen bond with adenine in the gas phase, but that the total energy of the complex in vacuo is only one-fourth to onethird that of the energy of thymine-adenine. 35,63,64 In water the H-bonding free energy would undoubtedly be less favorable due to shielding by the higher dielectric constant and especially by competition with hydrogen bonds to water. The conclusion that difluorotoluene is hydrophobic and poor at forming hydrogen bonds is also supported by the fact that it is strongly destabilizing in DNA when paired with natural bases and shows little if any inherent pairing selectivity for adenine over the other bases.…”