Reinvestigation of the Conformation of Cyclosporin A in Chloroform

New investigations of cyclosporin A in CDCl3 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 βII′-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 χ1 torsion), in contrast to the old structure, where the side chain is extended away from the backbone.

[1]  T. Chakraborty,et al.  A stereospecific synthesis of (4R)-4-[(E)-2-butenyl]-4,N-dimethyl-L-threonine (MeBmt) , 1988 .

[2]  Garland R. Marshall,et al.  THE GENERATION OF THREE-DIMENSIONAL STRUCfURES FROM NMR-DERIVED CONSTRAINTS , 1989 .

[3]  R. Wenger.  Synthesis of cyclosporine. Total syntheses of ‘cyclosporin A’ and ‘cyclosporin H’, two fungal metabolites isolated from the species Tolypocladium inflatum GAMS , 1984 .

[4]  W F van Gunsteren,et al.  A molecular dynamics study of the C-terminal fragment of the L7/L12 ribosomal protein. Secondary structure motion in a 150 picosecond trajectory. , 1985, Journal of molecular biology.

[5]  U. Schmidt,et al.  Synthesis of (4)-4-(()-2-butenyl)-4,-dimethyl--threonine (MeBMT), the characteristic amino acid of cyclosporine , 1987 .

[6]  Synthese von Cyclosporin und Analoga: Zusammenhang zwischen Struktur und immunsuppressiver Aktivität , 1985 .

[7]  Davidr . Evans,et al.  Asymmetric glycine enolate aldol reactions: synthesis of cyclosporin's unusual amino acid, MeBmt , 1986 .

[8]  Armin Widmer,et al.  Peptide conformations. Part 31. The conformation of cyclosporin a in the crystal and in solution , 1985 .

[9]  V. Bystrov.  Spin—spin coupling and the conformational states of peptide systems , 1976 .

[10]  G. P. Meier,et al.  A semi-synthetic approach to olefinic analogs of amino acid one (MeBMT) in cyclosporin A , 1989 .

[11]  Horst Kessler,et al.  Two‐Dimensional NMR Spectroscopy: Background and Overview of the Experiments [New Analytical Methods (36)] , 1988 .

[12]  D. G. Davis,et al.  Separation of chemical exchange and cross-relaxation effects in two-dimensional NMR spectroscopy , 1985 .

[13]  R. Kaptein,et al.  Determination of biomolecular structures from proton-proton NOE's using a relaxation matrix approach , 1988 .

[14]  D. Rich,et al.  Total synthesis of the unusual cyclosporine amino acid MeBMT , 1987 .

[15]  W. Vangunsteren,et al.  CONFORMATIONAL DYNAMICS DETECTED BY NUCLEAR MAGNETIC-RESONANCE NOE VALUES AND J-COUPLING CONSTANTS , 1988 .

[16]  Rolf Boelens,et al.  Iterative procedure for structure determination from proton-proton NOEs using a full relaxation matrix approach. Application to a DNA octamer , 1989 .

[17]  J M Blaney,et al.  Calculating three-dimensional molecular structure from atom-atom distance information: cyclosporin A. , 2009, International journal of peptide and protein research.

[18]  D. Seebach,et al.  Complexation and medium effects on the conformation of cyclosporin A studied by NMR spectroscopy and molecular dynamics calculations. , 1990, Biochemical pharmacology.

[19]  D. Rich,et al.  Molecular mechanics calculations of cyclosporin A analogues: effect of chirality and degree of substitution on the side-chain conformations of (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoic acid and related derivatives , 1989 .

[20]  W F van Gunsteren,et al.  On the dependence of molecular conformation on the type of solvent environment: A molecular dynamics study of cyclosporin A , 1990, Biopolymers.

[21]  H. Loosli,et al.  Neue Cyclosporine aus Tolypocladium inflatum. Die Cyclosporine K–Z† , 1987 .

[22]  A. Ganguly,et al.  Cyclofunctionalisation of epoxyalcohol derivatives. 4. Cyclisation of sulfonylacetate dianions: A synthesis of “MeBMT” , 1989 .

[23]  H. Loosli,et al.  [Cyclosporin A, a Peptide Metabolite from Trichoderma polysporum (Link ex Pers.) Rifai, with a remarkable immunosuppressive activity]. , 1976, Helvetica chimica acta.

[24]  Horst Kessler,et al.  Peptide conformations. Part 30. Assignment of the 1H‐, 13C‐, and 15N‐NMR spectra of cyclosporin A in CDCl3 and C6D6 by a combination of homo‐ and heteronuclear two‐dimensional techniques , 1985 .

[25]  Horst Kessler,et al.  Molecular dynamics simulations of cyclosporin A: The crystal structure and dynamic modelling of a structure in apolar solution based on NMR data , 1987, J. Comput. Aided Mol. Des..

[26]  D. Rich,et al.  A short synthesis of enantiomerically pure (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoic acid, the unusual C9 amino acid found in the immunosuppressive peptide cyclosporine , 1987 .

[27]  G R Marshall,et al.  Structures from NMR distance constraints. , 1990, Biochemical pharmacology.

[28]  G. Rose,et al.  Turns in peptides and proteins. , 1985, Advances in protein chemistry.

[29]  T. Chakraborty,et al.  A versatile protocol for β-hydroxy-α-amino acids: an application to (4R)-4-[(e)-2-butenyl]-4n-dimethyl-l-threonine (MeBmt) , 1989 .

[30]  A. Wand,et al.  Model-independent and model-dependent analysis of the global and internal dynamics of cyclosporin A , 1989 .

[31]  R. Traber,et al.  Die Struktur von Cyclosporin C , 1977 .

[32]  S. Chandrasekhar,et al.  Highly stereoselective approach for β-hydroxy-α-amino acids from d-glucose : The synthesis of MeBmt , 1989 .

[33]  R. Wenger.  Synthesis of Cyclosporine. Part II. Synthesis of Boc‐D‐Ala‐MeLeu‐MeLeu‐MeVal‐OH, a part of the peptide sequence of cyclosporine, by different strategic ways and synthesis of its isomers Boc‐D‐Ala‐MeLeu‐D‐MeLeu‐MeVal‐OH, Boc‐D‐MeLeu‐DMeVal‐OH, and Boc‐D‐Ala‐MeLeu‐MeLeu‐D‐MeVal‐OH as reference compoun , 1983 .

[34]  R. Wenger.  Synthesis of Cyclosporine. I. Synthesis of enantiomerically pure (2S,3R,4R,6E)‐3‐hydroxy ‐4‐methyl‐2‐methylamino‐6‐octenoic acid starting from tartaric acid , 1983 .

[35]  C. Griesinger,et al.  Peptide conformations. 42. Conformation of side chains in peptides using heteronuclear coupling constants obtained by two-dimensional NMR spectroscopy , 1987 .