Binding mechanisms of TATA box-binding proteins: DNA kinking is stabilized by specific hydrogen bonds

One of the common mechanisms of DNA bending by minor groove-binding proteins is the insertion of protein side chains between basepair steps, exemplified in TBP (TATA box-binding protein)/DNA complexes. At the central basepair step of the TATA box TBP produces a noticeable decrease in twist and an increase in roll, while engaging in hydrogen bonds with the bases and sugars. This suggests a mechanism for the stabilization of DNA kinks that was explored here with ab initio quantum mechanical calculations and molecular dynamics/potential of mean force calculations. The hydrogen bonds are found to contribute the energy necessary to drive the conformational transition at the central basepair step. The Asn, Thr, and Gly residues involved in hydrogen bonding to the DNA bases and sugar oxygens form a relatively rigid motif in TBP. The interaction of this motif with DNA is found to be responsible for inducing the untwisting and rolling of the central basepair step. Notably, direct readout is shown not to be capable of discriminating between AA and AT steps, as the strength of the hydrogen bonds between TBP and the DNA are the same for both sequences. Rather, the calculated free energy cost for an equivalent conformational transition is found to be sequence-dependent, and is calculated to be higher for AA steps than for AT steps.