Solution structure and dynamics of the A-T tract DNA decamer duplex d(GGTAATTACC)(2): implications for recognition by minor groove binding drugs

The structure of the DNA decamer duplex d(GGTAATTACC)(2) has been determine d using NMR distance restraints and molecular dynamics simulations of 500 p s to 1 ns in aqueous solution at 300 K. Using both canonical A and canonica l B starting structures [root-mean-square deviation (RMSD) 4.6 K; 1 Angstro m = 10(-10) m], with and without experimental restraints, we show that all four simulations converge to a similar envelope of final conformations with B-like helical parameters (pairwise RMSD 1.27-2.03 Angstrom between time-a veraged structures). While the two restrained simulations reach a stable tr ajectory after 300-400 ps, the unrestrained trajectories take longer to equ ilibrate. We have analysed the dynamic aspects of these structures (sugar p ucker, helical twist, roll, propeller twist and groove width) and show that the minor groove width in the AATT core of the duplex fluctuates significa ntly, sampling both wide and narrow conformations. The structure does not h ave the highly pre-organized narrow minor groove generally regarded as esse ntial for recognition and binding by small molecules, suggesting that ligan d binding carries with it a significant component of 'induced-fit', Our sim ulations show that there are significant differences in structure between t he TpA step (where p = phosphate) and the ApA and ApT steps, where a large roll into the major groove at the TpA step appears to be an important facto r in widening the minor groove at this position.