A conformational exploration of the protonated and unprotonated macrolide antibiotic roxithromycin: comparative study by molecular dynamics and NMR spectroscopy in solution

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Abstract
Molecular dynamics simulations (MD) have been performed on protonated and unprotonated roxithromycin, a novel macrolide antibiotic, using the crystallographic coordinates as the starting conformation in order to understand conformational changes. In all cases the 100 ps time scale seemed adequate for sampling an ensemble of solution conformers. Roxithromycin did not unfold appreciably during a 100 ps simulation while, for the protonated form, the desosamine unit underwent an interesting conformational reorganization (‘a⇔c’) during its evolution from the crystal structure form. MD indicate insignificant folding relative to the C(3)–C(5) region and it is believed that the necessary activation energy for this observed transitional event (‘A⇔B’) is probably not attained in solution, in contrast with erythromycin A. Long-range 13C–1H coupling constants are reported and correlated to the glycosidic torsional angles. The use of MD simulation has facilitated the confirmation of solution conformation as predicted by NMR spectroscopy. Moreover, it gives structural information on the different conformers present in solution. The data are not compatible with the conformation observed in the crystal structure only, and support a single conformation model Aa for roxithromycin with two types of hydrogen bonding (II and III). However, conformational averaging of Aa and Ac can give good agreement between theoretical and experimental data for the protonated analogue. The different values of potential energies for the observed low-energy conformers support the importance of hydrogen bonding in macrolide conformation. It appears that intra-residue hydrogen bonding, such as type III, 11-OH///OC (1), plays a role in determining the conformation of a large region [from C(9) to C(1)] of the antibiotic macrolide. Roxithromycin probably exists in the form of two ring-conformers ‘AII⇔AIII’ and, in CDCl3, a hydrogen bridge is formed that lowers the barrier enough to make interconversion possible.

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