The intrinsic rotational barriers of the alpha and zeta coordinates of the native and modified DNA linkages were examined using neutral and ionic methyl phosphates, phosphorothioates, and phosphonates as model systems. Free energy profiles of the pathways from the right- (g(-)g(-)) to the left-handed (gg) conformers of dimethyl phosphate anion (CH3OP(O-2)OCH3-), dimethyl phosphorothioate anion (CH3OP(O)(S)OCH3-), dimethyl methylphosphonate (CH3OP(O)(CH3)OCH3), and methyl ethylphosphonate anion (CH3CH2P(O-2)OCH3) were evaluated using ab initio MP2/6-31 G+G**//HF/6-31G* quantum mechanical calculations coupled with the Langevin dipoles and polarized continuum solvation models. Differences in the gas-phase conformational properties of the studied molecules were found to diminish in aqueous solution. In solution, the,og (g-g-) conformations are the most stable for dimethyl phosphate anion and the neutral phosphonate, whereas the gt conformation was predicted to prevail for dimethyl phosphorothioate anion. For methyl ethylphosphonate anion, which was found to be the most flexible of all the studied molecules, three stable conformations involving the gg, gt(-), and t(-)g rotamers were predicted. The calculated activation free energies for the g(-)g(-) <-> gg transition in aqueous solution amount to 2.7, 1.7, 2.1, and 1.5 kcal/mol for the dimethyl phosphate anion, dimethyl phosphorothioate anion, and the neutral and ionic phosphonate ester, respectively. For the S-p and R-p stereoisomers of the DNA linkage containing the neutral phosphonate, the structures of the corresponding transition states involve the cis conformation around the PO3＇ or PO5＇ bonds, respectively. The calculated similarities in the conformational behavior of the phosphate, phosphorothioate, and phosphonate methyl esters are quite informative. In particular, they provide formal justification for the use of the substitution experiments to study the role of intermolecular interactions involving ionic and ester phosphate oxygens in the stabilization of the structure of nucleic acids and DNA-protein complexes.