Molecular Dynamics Simulations of Novel Hoogsteen-Like Bases That Recognize the T-A Base Pair by DNA Triplex Formation

Effective sequence-specific recognition of duplex DNA is possible by tripler formation with natural oligonucleotides via Hoogsteen H-bonding. However, tripler formation is in practice limited to pyrimidine oligonucleotides binding duplex A-T or G-C base pair DNA sequences specifically at homopurine sites in the major groove as T . A-T and C+. G-C triplets. Here we report the successful molecular dynamics modelling of novel unnatural nucleosides that recognize the T-A DNA base pair by Hoogsteen interaction, These X . T-A triplets were placed within (T . A-T)(11) triplexes of A-type or B-type starting configuration. These tripler structures underwent energy minimization and 300 ps molecular dynamics simulation with counter-ions and solvent. The same procedures were applied to unmodified (T . A-T)(11) triplexes and their trajectories compared to those oi the central triplet modified triplexes of similar starring configuration, The phosphodiester backbone dihedrals, chi-dihedrals, and H-bonding distances of the central and adjacent triplets of the modified and unmodified triplexes show similar average values and deviations from starting configurations. This indicates that these X . T-A triplets do not induce any significant perturbations for the duration of the simulation.