Spatial structure of cyclosporin A and insight into its flexibility

The molecule of immunosuppressant drug cyclosporin A (CsA) exhibits different properties when dissolved in different media. In apolar solvents it is stabilized by intramolecular hydrogen bonds, but there also exist some less populated conformations. Existence of minor forms is clearly seen from 1H NMR spectra.Using nuclear Overhauser effect (NOE) spectroscopy and analysis of residual dipolar couplings, we obtained data on the molecular structure of the dominant conformers. Based on these data, the spatial structure of the main conformer of cyclosporin in chloroform was determined by molecular dynamics simulation. The kinetics of exchange between the major and minor forms was also studied. Energy barrier (ΔG‡) between the two states is 81 ± 2 kJ/mol. The conformation of CsA in complex with sodium dodecyl sulphate micelles was determined from NOE data.Use of independent structural data improves the reliability of the simulated results. The structure of the minor forms, which exist in organic solvents and also in micellar solution, cannot be assessed by means of nuclear magnetic resonance. Spectroscopic and thermodynamic parameters, however, point to their certain properties. In particular, the minor conformer of CsA in chloroform differs from the main one by a peptide bond (in cis- rather than trans-conformation) in the region of residues from 4 to 7.

► Structures of cyclosporin A in CHCl3 and in complex with SDS micelles are determined.
► Thermodynamic parameters of conformational exchange in CHCl3 are found.
► Residual dipolar couplings and NOE are used as a source of structural information.