Unrestrained molecular dynamics of photodamaged DNA in aqueous solution

The structural impact of photolesions on DNA was investigated by carrying Out molecular dynamics simulations of the T5/T6 cis-syn dimer (A), T5/T6 6-4 adduct (B), and native decamer (C) of d(CGCATTACGC)(2). For the cis-syn dimer containing decamer the simulations provided a structure very similar to that derived with experimental NOE data. Specifically, distortions of the simulated cis-syn dimer duplex (A) were primarily localized at the lesion site and had an overall bend similar to that of the refined NMR structure. For the simulated 6-4 adduct duplex (B), although there was considerable coincidence with the NMR derived structure, an intact hydrogen bond/dipole-dipole interaction between the T6 pyrimidone carbonyl oxygen and A15/NH2 was observed, which was not found in the NMR derived structure. This hydrogen bond leads to a structure that seems to better account for some of the unusual experimental NOEs than the refined NMR structure. In addition, for the 6-4 adduct (B), the overall bend was significantly smaller than that suggested by the NMR derived structure. This difference in overall bend is presumably a result of differences in the torsion angles at the lesion site for the simulated vs the experimental structure. Overall these simulations agreed well with the features of the spectroscopically determined structures and reveal the power of molecular dynamics methods with explicit solvation and accurate representation of long-range electrostatic interactions to usefully model noncanonical forms of DNA.