Conformational Flexibility of Phosphate, Phosphonate, and Phosphorothioate Methyl Esters in Aqueous Solution

The intrinsic rotational barriers of the α and ζ 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(O2)OCH3-), dimethyl phosphorothioate anion (CH3OP(O)(S)OCH3-), dimethyl methylphosphonate (CH3OP(O)(CH3)OCH3), and methyl ethylphosphonate anion (CH3CH2P(O2)OCH3) were evaluated using ab initio MP2/6-31G+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 gg (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 ethylph...