Interaction of the mutagenic base analogs O⁶‐methylguanine and N⁴‐hydroxycytosine with potentially complementary bases

Infrared spectroscopy has been employed to study possible base pair interactions, in nonpolar media, between O 6 ‐methylguanine and uracil, cytosine and adenine; and between derivatives of N 4 ‐hydroxycytosine and adenine. The association constants of O 6 ‐methylguanine with uracil, cytosine, and adenine are well below 1 M –1 , whereas those for interaction of 1‐methyl‐N 4 ‐methoxycytosine and its 5‐methyl derivative with adenine are identical, K = 14 M –1 . The significance of the latter finding is discussed in relation to the conformation of the exocyclic N 4 ‐methoxy group. Quantum chemical calculations, with the aid of the perturbation method, were carried out for the interaction of O 6 ‐methylguanine with uracil, cytosine, and adenine, to establish the most energetically favoured configurations for interactions of the free bases, and of the same base pairs in the B form of DNA. The role of the conformation of the exocyclic —OCH 3 group in O 6 ‐methylguanine is discussed. The relevance of both the experimental and theoretical results to mutagenesis by O 6 ‐methylguanine and N 4 ‐hydroxycytosine is examined.