Nanosecond molecular dynamics of zipper-like DNA duplex structures containing sheared G center dot A mismatch pairs

Molecular dynamics (MD) simulations are presented of an unusual DNA duplex structure with the sequence d(GCGAAGC)(2) that adopts a central zipper moti f 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 geo metry at its end. On a nanosecond scale, the simulations show very stable t rajectories and not only the Watson-Crick base pairs but also the central u npaired adenine zipper are revealed as predominantly rigid segments of the molecule. The sheared G . A mismatch base pairs in contrast are nonplanar a nd flexible, and bending of the structure can occur at the mismatch junctio ns. The pronounced flexibility of the sheared G . A mismatches is explained as a result of their intrinsic nonplanarity rather than being a consequenc e of any interactions with neighboring residues. The simulations clearly sh ow that sheared G . A mismatches require extensive stacking with adjacent b ase pairs for their maintenance. Two stable local conformational substates of the d(GCGAAAGC)2 zipper molecule are suggested by the simulations, invol ving cation-stabilized clustering of three negatively charged phosphate gro ups in the zipper region accompanied by adjustment of adenine stacking, sug ar repuckering, and the presence of several highly ordered hydration sites with close to 100% occupancy and long-residing water molecules. Further, th e capability of the zipper motif to incorporate guanine, cytosine, or thymi ne residues is tested. All simulations were carried out with the AMBERS pro gram with a force field created by Cornell et al. (Cornell, W. D.; et al. J . Aln. Chem. Sec. 1995, 117, 5179) using the particle mesh Ewald (PME) tech nique for electrostatic interactions, with a total length reaching 30 ns. T he overall results confirm an excellent performance of the PME MD technique and of the force field of Cornell ct al, for unusual nucleic acid conforma tions.