Reinvestigation of the Conformation of Cyclosporin A in Chloroform

Abstract

New investigations of cyclosporin A in CDCl, have been performed to obtain additional and more accurate distance restraints than utilized in our previous studies of cyclosporin A. Build-up rates at 600 MHz using 6 different mixing times at low temperatures (252.5 K) were determined and transformed into distances using the two-spin approximation. With the new distance restraints in the MD simulations using the GROMOS package, we can unambiguously conclude the presence of a ,6II'-turn. The new structure resembles the X-ray structure more than the structure previously determined, especially regarding the orientation of the MeBmt side chain. In the new structure and in the solid state, the side chain is folded over the backbone (although there are substantial differences in the xI torsion), in contrast to the old structure, where the side chain is extended away from the backbone.Some years ago, we studied the conformation of cyclosporin A in CDCl, by NMR spectroscopy [I-41. In [lo] and another calculation algorithm which scans the total conformational space better than conventional MD methods [1 11 were applied to this molecule.

Insights into the Unique Phosphorylation of the Lasso Peptide Paeninodin

“…In addition, we propose that these co-existing conformations undergo rapid chemical exchange, which results in overlapping signals and hinders NMR structure determination. A few natural peptides were shown to assume multiple, stable, and distinct conformations; in these cases, NMR structure solution was possible albeit challenging (37)(38)(39). As the thermal instability of paeninodin prevented the recording of NMR spectra at higher temperatures, structure determination was deemed outside the scope of this study.…”

Active site mutants of human cyclophilin A separate peptidyl‐prolyl isomerase activity from cyclosporin A binding and calcineurin inhibition

“…Walsh, unpubl.). It is likely that the mutant CyPs selectively bind the trans conformation of CsA, which exists in solution (Kessler et al, 1990;Altschuh et al, 1992) and has recently been shown to be the active species for PPIase inhibition (Kofron et al, 1992). In this view, the CyP active site serves solely as a scaffolding apparatus to present bound drug in an active conformation.…”

“…The structure of CsA bound to CyP has recently been determined by NMR analysis Weber et al, 1991) and differs dramatically from CsA in solution (Kessler et al, 1990). Specifically, the 9,lO-amide bond is trans when bound and cis in solution.…”

Optimisation of metric matrix embedding by genetic algorithms

“…The performance of D G Q was compared with that of D G II, using cyclosporin A (CPA) (Lautz et al, 1987(Lautz et al, , 1989Kessler et al, 1990) as the target molecule for struc ture elucidation. The aim of this research was to present the principles underlying D G Q and to demonstrate that the approach can be used to generate improved struc tures.…”