Assessing the Sequence Dependence of Pyrimidine-Pyrimidone (6-4) Photoproduct in a Duplex Double-Stranded DNA: A Challenge for Microsecond Range Simulation

Sequence dependence of the (6-4)photoproduct dynamics when embedded in six 25-bp duplexes is evaluated along extensive unbiased and enhanced (replica exchange with solute tempering, REST2) molecular dynamics simulations. The structural reorganization as the central pyrimidines become covalently tethered is traced back in terms of non-covalent interactions, DNA bending and extrusion of adenines of the opposite strands. The close sequence pattern impacts the conformational landscape around the lesion, inducing a different upstream and downstream flexibilities. Moreover, REST2 simulations allow to probe structures possibly important for damaged DNA recognition.