Nanosecond Molecular Dynamics of Zipper-like DNA Duplex Structures Containing Sheared G·A Mismatch Pairs

Molecular dynamics (MD) simulations are presented of an unusual DNA duplex structure with the sequence d(GCGAAAGC) 2 that adopts a central zipper motif of four unpaired and mutually intercalated adenines enveloped by sheared G·A mismatch base pairs and Watson−Crick G·C base pairs with B-form geometry at its end. On a nanosecond scale, the simulations show very stable trajectories and not only the Watson−Crick base pairs but also the central unpaired adenine zipper are revealed as predominantly rigid segments of the molecule. The sheared G·A mismatch base pairs in contrast are nonplanar and flexible, and bending of the structure can occur at the mismatch junctions. The pronounced flexibility of the sheared G·A mismatches is explained as a result of their intrinsic nonplanarity rather than being a consequence of any interactions with neighboring residues. The simulations clearly show that sheared G·A mismatches require extensive stacking with adjacent base pairs for their maintenance. Two stable local conformational substates of the d(GCGAAAGC) 2 zipper molecule are suggested by the simulations, involving cation-stabilized clustering of three negatively charged phosphate groups in the zipper region accompanied by adjustment of adenine stacking, sugar repuckering, and the presence of several highly ordered hydration sites with close to 100% occupancy and long-residing water molecules. Further, the capability of the zipper motif to incorporate guanine, cytosine, or thymine residues is tested. All simulations were carried out with the AMBER5 program with a force field created by Cornell et al. (Cornell, W. D.; et al. J. Am. Chem. So c. 1995, 117, 5179) using the particle mesh Ewald (PME) technique for electrostatic interactions, with a total length reaching 30 ns. The overall results confirm an excellent performance of the PME MD technique and of the force field of Cornell et al. for unusual nucleic acid conformations.