Free Energy Coupling between DNA Bending and Base Flipping.

Free energy simulations are presented to probe the energetic coupling between DNA bending and the flipping of a central thymine in double stranded DNA 13mers. The energetics are shown to depend on the neighboring base pairs, and upstream C or T or downstream C tended to make flipping more costly. Flipping to the major groove side was generally preferred. Bending aids flipping, by pushing the system up in free energy, but for small and intermediate bending angles the two were uncorrelated. At higher bending angles, bending and flipping became correlated, and bending primed the system for base flipping toward the major groove. Flipping of the 6-4 pyrimidine-pyrimidone and pyrimidine dimer photoproducts is shown to be more facile than for undamaged DNA. For the damages, major groove flipping was preferred, and DNA bending was much facilitated in the 6-4 pyrimidine-pyrimidone damaged system. Aspects of the calculations were verified by structural analyses of protein-DNA complexes with flipped bases.