Nanosecond Molecular Dynamics of Hybrid Triplex and Duplex of Polycation Deoxyribonucleic Guanidine Strands with a Complimentary DNA Strand

Abstract

Replacement of the phosphodiester linkages of the polyanion DNA with guanidinium linkers provides the polycation deoxyribonucleic guanidine (DNG). Molecular dynamics studies to 1120 ps of the hybrid triplex and 1420 ps of the hybrid duplex formed from octameric DNG strands d(Tg)8 with a complementary DNA oligomer strand d(Ap)8 have been carried out with water explicitly as solvent and Na+Cl- as counterions under periodic boundary conditions using the CHARMM force field and Ewald summation method. The Watson−Crick and Hoogstein hydrogen-bonding patterns of the A/T tracts remained intact without any structural restraints for both hybrid duplex and triplex structures throughout the simulation. And for the hybrid duplex and triplex structures, both 5‘ and 3‘ ends were only partially frayed. In agreement with our previous thermodynamic study the hybrid triplex is more favorable than the hybrid duplex in the simulations. This conclusion is reached by the comparison of the extent of 5‘ end fraying and the bifurcating properties of the two systems. The structural histories of the DNG·DNA·DNG triplex and DNG·DNA duplex were determined by examining histograms from the last 1400 ps (duplex) and 1100 ps (triplex) of the dynamics run. These include the hydrogen-bonding pattern (sequence recognition) and base pair opening occurrences, minor groove width narrowing, and tract bending for the hybrid duplex and triplex structures. The bending angle measured between the local axis vectors of the first and last helical axis segments is about 30° for the averaged structures of both hybrid duplex and Watson−Crick portion of the hybrid triplex. Propeller twist (associated with three centered hydrogen bonding) up to −30°, native to DNA AT base pairing, was also observed for the duplex structure. The helical rise and twist parameters of the duplex structure and the duplex portion of the triplex structure assume a more B-DNA like conformation. However, the sugar pucker and other helical, axis, and base pair parameters of the two structures equilibrate at a A and B complex conformation, from base to base and base pair to base pair, which suggests a more A-DNA like overall conformation. Water spines are observed during the dynamics runs for both hybrid duplex and triplex structures in both minor and major grooves. The counterions remain in their positions through the dynamics run for the triplex system.