Harmonizing Interstrand Electrostatic Repulsion by Conformational Rigidity in Counterion-Deprived Z‑DNA: A Molecular Dynamics Study

Deoxyribonucleic acid (DNA) is a vital biomacromolecule. Although the right-handed B-DNA type helical structure is the most abundant and extensively studied form of DNA, several noncanonical forms, such as triplex, quadruplex, Z-DNA, A-DNA, and ss-DNA, have been probed from time to time to gain insights into the DNA’s function. Z-DNA was recently found to be involved in cancer and several autoimmune diseases. In the present Article, we evaluated the conformational stability of locked-sugar-based Z-DNA via all-atom explicit-solvent molecular dynamics simulations and found that the modified DNA maintained the left-handed conformation even in the absence of counterions, wherein the structural rigidity dominates over the electrostatic repulsion between the complementary strands. The control Z-DNA without counterions, as expected, instantaneously resulted in unfolded states. The remarkable stability of the conformationally locked model system was thoroughly investigated via structural and energetic perspectives and was probably the result of the backbone widening in tandem with enhanced electrostatics between complementary strands. We believe that the design of the proposed modified Z-DNA construct could help understand the otherwise delicate Z-DNA conformation even in salt-deprived conditions. The design could also motivate the medicinal use of short segments of such modified nucleotides and could be utilized in more advanced modeling techniques, such as DNA origami which has gained popularity in recent years.