Fidelity of nucleic acid biosynthesis. Computer study of the role of DNA polymerases in mispairing of modified bases

Computer modeling was employed to interpret the observed substrate and template properties of modified bases: 8-oxoguanine (OG), 8-oxoadenine (OA), 6-methylguanine (m(6)G), 3-methylguanine (m(3)G), and 2-aminopurine (aP). Energy calculations were made for the interaction of the incorporating nucleotide with the DNA template base and a model DNA polymerase recognition center containing two OH groups fixed in positions corresponding to hydrogen bonding with purine N3 and pyrimidine O2 of Watson-Crick pairs. The computations explained the high probability of OG:A and lack of OG:G pairing, during DNA biosynthesis on an OG-containing template or with OGTP as substrate, as well as the low mutagenicity of OA as compared with OG. The high frequency of m(6)G-induced transitions could be attributed to H-bonding between the polymerase recognition center and m(6)G:C or m(6)G:T pairs, whereas the lack of m(3)G mutagenicity was due to the impossibility of such bonding. Explanation was also obtained for the ambiguous coding properties of aP and the fact that the frequencies of aP:T pairing by various polymerases differ much less than those of aP:C.