Options for interstrand DNA duplex linkages have been studied by incorporating transition metal ions in the ligand-functionalized LNA (locked nucleic acid) duplexes. The effect of first-row transition metal ions (M = Ni-2+,Ni- Cu2+, and Zn2+) on the geometries and formation energies of mono- and dimetallic model complexes was calculated by DFT methods, and the results were compared with available experimental data. The results showed a clear preference for the formation of copper complexes over the corresponding nickel and zinc complexes, in agreement with the trends observed in the denaturation temperatures of the ligand-functionalized LNA duplexes. In addition, dichloride bridged dimeric complex, [(LCu)-Cu-LNA(mu-Cl)(2)CuLLNA](2+), in which L-LNA is N,N-bis(2-pyridylmethyl)-beta-alanyl functionalized LNA, was found energetically very stable, providing a potential structural option for an interstrand duplex linkage. The model complex and its simpler structural analogues were synthesized and structurally characterized. Comparison of the dimeric linker introduced into duplex tetramer strands, which provided a computational model for a double helix with two closely located LNA units, with a similar model for mononuclear Cu(L-LNA)(2)(2+) linker also showed a clear preference of the dichloride-bridged option, suggesting that the [(LCu)-Cu-LNA(mu-Cl)(2)CuLLNA](2+) complex produced a chemically realistic model to explain duplex stabilization in the presence of Cu2+ and excess Cl-.