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, DDRP) 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 ansa backbone. It has been shown that favourable or unfavourable conformations of the ansa chain in rifamycin crystals are generally diagnostic of activity or inactivity against isolated DDRP. The principles of structure correlation suggest that the torsional variety observed in rifamycin crystals should 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 angles is analysed. Active compounds show a well-defined common pattern, while non-active molecules are more scattered, mainly due to steric constraints forcing the molecules into unfavourable conformations. The experimental distributions of torsion angles are compared to the torsional freedom of the ansa chain simulated by molecular dynamics calculations performed at different temperatures and conditions on rifamycin S and rifamycin O, which represent a typical active and a typical sterically constrained molecule, respectively. It is shown that the torsional variety found in the crystalline state samples the dynamic behaviour of the ansa chain for active compounds. The methods of circular statistics are illustrated to describe torsion angle distributions.