DNA base sequence specificity through partial intercalation: DFT-D based energy analysis of molecular dynamics snapshots.

Abstract It had been observed that in some DNA-binding proteins, hydrophobic amino acid side-chains intercalate between two base pairs of the DNA, often leading to curvature or kink. Some of these proteins pre-dominantly interact through the minor groove and are often described as not having strong sequence preference. In contrast, lac-repressor binds to DNA with strong sequence specificity, also interacts with the minor groove of its operator by partially intercalating two Leucine side-chains between two CG base pairs, in addition to its interaction with the major groove base atoms. The role of this interaction in the operator recognition has not been fully elucidated. We have done extensive quantum chemical calculations, from molecular dynamics derived snapshots, using dispersion-corrected density functional theory to show that this unstacking is energetically slightly unfavorable. However, among all the base-amino acid pairs studied, the CG/CG-Leucine pair, the natural sequence, is among the most stable ones. The bending of the DNA resulting from this intercalation is important for aligning the major dimeric protein and the DNA interfaces. Thus, the sacrifice of modest binding energy enhances the sequence-specificity. Given many prokaryotic repressors belong to the lac repressor family, this could be a general mechanism for augmenting sequence specificity.