Ab initio distributed multipole electrostatic calculations are used to predict likely nucleic acid base pair structures for both the gas phase and within a double helical backbone, as represented by simple constraints. The resulting structures are interpreted by comparison with an analysis of the experimental variation of base pair geometries found in oligonucleotide crystals. Our calculations on all pairs of the normal bases (G, A, T, C) correctly predict all the multiply hydrogen-bonded structures, in agreement with supermolecule SCF calculations, and also predict some new low-energy structures. Consideration of the helical constraints confirms that the Watson–Crick G · C and A · T pairings are most favourable for inclusion in DNA, but certain mismatch base pairs, G · T and G. · A, are also energetically favourable and their geometries correspond to the experimentally observed wobble conformations. This approach is also used to study the effect of the O⁶ methylation of guanine which can form a doubly hydrogen-bonded Watson–Crick-like structure with thymine. However, there are also a range of O⁶-methylguanine · cytosine structures which fit into the helical backbone and are energetically competitive. Thus the mutation-inducing effects of this base modification are likely to be very sensitive to the exact sequence and local conformation of the DNA.