Computed conformational analysis of lipoxins and their ionic complexes.

The possible molecular conformations of four structurally and biologically different lipoxins derivatives were predicted by a systematic structure tree theoretical analysis. This method takes into account the London-Van der Waals energy of interaction, the electrostatic interaction, the rotation energy of the torsional angles and the energy of transfer through a possible lipid-water interface. Finally, the conformers derived from the structure tree and with a high probability of existence were submitted to the energy minimization procedure. The most probable conformers of lipoxin A: 5S,6R,15S-trihydroxy-7,9,13 trans-11 cis-eicosatetraenoic acid (LXA); 11 trans lipoxin A: 5S,6R,15S-trihydroxy-7,9,11,13 trans-eicosatetraenoic acid (11t-LXA); lipoxin B: 5S,14R 15S-trihydroxy-6,10,12 trans-8 cis-eicosatetraenoic acid (LXB) and 8 trans lipoxin B: 5S,14R,15S-trihydroxy- 6,8,10,12 trans-eicosatetraenoic acid (8t-LXB) in their isolated form or when forming complexes with one calcium ion are presented. The four isolated compounds lead to vastly different conformations. Lipoxin A can form the most globular conformer while lipoxin B seems to be slightly more extended. The all trans isomer of lipoxin B forms an extended conformer and 11 trans lipoxin A gives a fully extended molecule. Complexes of a pair of these compounds with one calcium ion were shown to lead to vastly different conformations. Both (LXA) 2Ca and (LXB)2Ca form crumpled or extended structure, the LXA molecules being more wrapped around Ca2+ than LXB molecules. The (11t-LXA)2Ca and (8t-LXB)2Ca complexes present a high probability of extended conformations. Our description merely shows that the peculiar stereochemistry of these molecules lead to equilibria between conformers or to very static conformers, the flexibility and rigidity of which being probably relevant in view of their different biological activities.