Transition-metal coordination modulates predicted DNA groove recognition and nucleobase contacts in oligohistidine complexes

Histidine-rich peptides are widely used in affinity-based purification because imidazole donors can coordinate transition-metal ions. To examine how fixed metal-coordination models may alter the predicted DNA-contacting behavior of a histidine hexamer, a fully in silico comparison was performed using metal-free His6 and the tri-metal model complexes [Zn3(His6)]6+, [Ni3(His6)]6+, and [Cu3(His6)]6+ against the canonical B-DNA dodecamer 1BNA [d(CGCGAATTCGCG)]. The formulas denote the neutral-terminal/neutral-imidazole computational representation used for docking and molecular dynamics (MD), rather than a claim concerning the dominant solution-phase species. Molecular docking and MD simulations were used to compare predicted groove localization, recurrent nucleobase-associated contacts, hydrogen-bond patterns, relative docking scores, and trajectory-based structural persistence. Within the examined 1BNA model, metal-free His6 produced a dominant major-groove pose with adenine-associated contacts and a Vina docking score of −8.9 kcal/mol. The tri-metal coordination models produced dominant minor-groove poses with guanine-associated contacts, with relative docking scores of −9.5, −13.5, and −10.8 kcal/mol for the Zn(II), Ni(II), and Cu(II) models, respectively. The Ni(II)- and Cu(II)-containing models also displayed lower RMSD levels than the metal-free complex over the sampled trajectories. These observations are restricted to the defined computational models and the 1BNA sequence; they do not establish experimental binding affinities, universal nucleobase selectivity, or solution-phase metal speciation. The work provides a hypothesis-generating comparison that may guide future experimental investigation of metal-coordinated oligohistidine-DNA interactions.