Erschienen in:
Helvetica Chimica Acta, 68 (1985) 3, Seite 682-704
Sprache:
Englisch
DOI:
10.1002/hlca.19850680319
ISSN:
1522-2675;
0018-019X
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>The all‐light‐atom X‐ray crystal‐structure analysis of cyclosporin A (<jats:bold>1</jats:bold>), a cyclic undecapeptide containing seven <jats:italic>N</jats:italic>‐methylated amino acids, reveals a conformation very similar to that of the previously analysed iodo derivative which is characterised by a twisted β‐pleated sheet involving the residues Me‐Val‐11, MeBmt‐1, Abu‐2, Sar‐3, MeLeu‐4, Val‐5, MeLeu‐6, and Ala‐7. The β‐bend at Sar‐MeLeu‐4 is of type II′, and the loop of the residual amino acids involves a cis‐peptide bond between MeLeu‐9 and MeLeu‐10. The NH proton of <jats:sc>D</jats:sc>‐Ala‐8 closes a <jats:italic>y</jats:italic><jats:sup>i</jats:sup>‐bend with a H‐bond to the MeLeu‐6 CO group. The crystal was grown from acetone. A closely similar backbone conformation in apolar solvents such as CDCl<jats:sub>3</jats:sub> or C<jats:sub>6</jats:sub>D<jats:sub>6</jats:sub> has been derived from the interpretation of the NMR spectral parameters (homo‐ and heteronuclear NOE effects, coupling constants, chemical‐shift values of the C‐, H‐, and N‐atoms). A minor variation in the backbone conformation between crystal and solution is observed in the region of <jats:sc>D</jats:sc>‐Ala‐8, where in solution a 3‐center H‐bond is established between the NH of <jats:sc>D</jats:sc>‐Ala‐8 und the carbonyl O‐atoms of both MeLeu‐6 (<jats:italic>y</jats:italic><jats:sup>i</jats:sup>‐turn) and <jats:sc>D</jats:sc>‐Ala‐8 (<jats:italic>C</jats:italic><jats:sub>5</jats:sub>‐bend). A recently proposed technique to identify intramolecular H‐bond <jats:italic>via</jats:italic> heteronuclear NOE from NH proton to carbonyl C‐atoms is critically analysed. The main difference between crystal and solution conformations lies in the orientation of the side chains of the unusual amino acid MeBmt (χ<jats:sub>1</jats:sub> = +60° in solution, ‐168° in the crystal) and of MeLeu‐10 (<jats:italic>X</jats:italic><jats:sub>1</jats:sub> = −60° in solution, +60° in the crystal). The differences in crystal and solution are caused by the break of the intermolecular H‐bond of the OH group of MeBmt on dissolution of the crystal. The bifurcated H‐bond of <jats:sc>D</jats:sc>‐Ala‐8 twists the backbone in this region. Molecular modeling demonstrates that this is the origin of the change in the side chain conformation of MeLeu‐10. The intramolecular flexibility in the crystal indicated by the thermal parameters obtained from the X‐ray refinement, and in solution by an analysis of spin‐lattice relaxation times in the NMR experiments, indicate a fairly rigid backbone and fixed conformations for all the side chains except for that of Abu‐2 and the distal atoms of MeBmt.</jats:p>