Theoretical study of the interaction of tetramethylammonium with double‐stranded oligonucleotides

Computations are performed on the interaction specificities of tetramethylammonium (TMA) for double‐stranded oligonucleotides held in the B conformation. The effects of base sequence and chain length are investigated. In the short oligomers (helices formed from dinucleoside monophosphates and trinucleoside diphosphates), the interaction energies of TMA are larger in the major groove of (dG) n · (dC) n than in the minor groove of either (dA) n · (dT) n or (dA—dT) n . Upon lengthening the oligomers, and owing to the gradual shaping of the grooves of the helix and cumulative effect of the phosphates, TMA is shown to increasingly favor the minor groove of (dA) n · (dT) n with respect to the major groove of (dG) n · (dC) n , with a sizeable energy difference computed at the pentanucleoside hexaphosphate level. The binding of TMA in the minor groove of (dA) n · (dT) n involves stabilizing contacts with several sites, on the bases and on the deoxyriboses. Configurations locating the cation closer to the thymine strand are slightly preferred over configurations locating it closer to the adenine strand.