Abstract
The conformational flexibility of the Z and E isomers of cefotaxime and thiazoximic acid, their ground state isomerisation path and transition state, were all analyzed in depth. The modeling was carried at the semi-empirical and DFT-BLYP level with geometry optimization. That approach was used after a thorough analysis using classical molecular dynamics to initially define large families of conformers. The lowest energy conformers always have an E configuration, in contradiction to the behaviour observed in solution, and the Z-E isomerisation mechanism is a rotation. These results reveal the remarkable flexibility of these molecules, allow anticipating the role of water and of their target proteins in the redistribution of the conformers population and provide the best geometry known for cefotaxime.