A hypothesis for what conformation of the major adduct of (+)anti-B[a]PDE(N-2-dG) causes G -> T versus G -> A mutations based upon a correlation between mutagenesis and molecular modeling results

Molecular modeling (simulated annealing) was used to study the conformation s in dsDNA of [+ ta]-B[a]P-N-2-dG (R.E.Kozack and E.L.Loechler, accompanyin g paper), which is the major benzo[a]pyrene (B[a]P) adduct, Sixteen classes of conformations were identified, and are analyzed herein vis-a-vis the tw o most prominent B[a]P mutations, G-->T and G-->A base substitutions. Eight conformations seem more relevant to frameshift mutagenesis, so they are ex cluded, leaving eight conformations as follows. Two conformations (BPmi5 an d BPmi3) retain Watson-Crick G:C base pairing having the B[a]P moiety of th e adduct in the minor groove, Two conformations (BPma5 and BPma3) have the Hoogsteen orientation with B[a]P in the major groove. Four conformations ar e base displaced and have B[a]P stacked in the helix with the dG moiety of the adduct displaced into either the major groove (Gma5 and Gma3) or the mi nor groove (Gmi5 and Gmi3), Three of these eight conformations (BPma5, BPma 3 and Gma3) are universally high in energy. The two conformations that reta in G:C base pairing potential (BPmi5 and BPmi3) are likely to be non-mutage nic. Of the three remaining conformations, Gmi5 can be relatively low in en ergy, but is distorted, A correlation exists between the calculated energie s for the remaining two base displaced conformations and mutagenesis for [ ta]-B[a]P-N2-dG, leading to the hypothesis that Gma5 is responsible for G- ->T mutations and Gmi3 is responsible for G-->A mutations. Gma5 and Gmi3 re semble each other, except that dG is in the major and minor grooves, respec tively. An incipient rationale for this hypothesis is discussed: DNA polyme rase might be triggered to follow a different mutagenic pathway depending u pon whether a non-informational lesion has bulk protruding into the major o r minor groove. A pathway for interconversion between these eight conformat ions is also proposed and its implications are discussed; e.g. four steps a re required to interconvert between Gma5 and Gmi3.