Conformational variety for the ansa chain of rifamycins: Comparison of observed crystal structures and molecular dynamics simulations

The antibiotic activity (via inhibition of DNA-dependent RNA polymerase, DD RP) of rifamycins has been correlated to the conformation of the ansa chain , which can be described by means of 17 torsion angles defined along the an sa backbone. It has been shown that favourable or unfavourable conformation s of the ansa chain in rifamycin crystals are generally diagnostic of activ ity or inactivity against isolated DDRP. The principles of structure correl ation suggest that the torsional variety observed in rifamycin crystals sho uld mimic the dynamic flexibility of the ansa chain in solution. Twenty-six crystal structures of rifamycins are grouped into two classes (active and non-active). For each class the variance of the 17 ansa backbone torsion an gles is analysed. Active compounds show a well-defined common pattern, whil e non-active molecules are more scattered, mainly due to steric constraints forcing the molecules into unfavourable conformations. The experimental di stributions of torsion angles are compared to the torsional freedom of the ansa chain simulated by molecular dynamics calculations performed at differ ent temperatures and conditions on rifamycin S and rifamycin O, which repre sent a typical active and a typical sterically constrained molecule, respec tively. It is shown that the torsional variety found in the crystalline sta te samples the dynamic behaviour of the ansa chain for active compounds. Th e methods of circular statistics are illustrated to describe torsion angle distributions.