Theoretical study of the self-association of amphotericin B

The aim of this present work is the study of self-association of amphotericin B (AmB) at a molecular level, because of its importance in the toxicity of this antibiotic. Molecular mechanics calculations have been performed considering different conformations of the polar head of AmB, the two most stable ones we have determined (B and C) and the one issued from the X-ray data. Our calculations have shown that both head-to-head and head-re-tail stable dimers were found within an energy range between - 30 and - 40 kcal/mol, the very stable head-to-head dimer with the polar head within C conformation having an energy of - 46.8 kcal/mol. We have shown that both electrostatic and Van der Waals terms contribute to the total interaction energy but their relative weight depends on the conformation of the polar head and on the head-to-head and head-to-tail structures involved in the dimer. Thus the electrostatic contribution does not particularly stabilize the head-to-tail dimer. Furthermore an explicit calculation of the dipole moment in the ground state of AmB has disproved the current assertion upon the greatest stabilization of head-to-rail dimers by electrostatic dipole-dipole interaction. Among all the dimers we have calculated, we have found a group denoted G1 with a geometrical structure consistent with absorption data, namely a blue-shift of the dimer main absorption band with regard to the monomer one. In this group G1 we have found two isoenergetic (- 38.8 kcal/mol) very stable head-to-head and head-to-tail dimers. We have found that, as a rule, the self-association of AmB in dimers is more favourable than the complexation with the cholesterol and, in a less extent, with the ergosterol. It seems that these features could be also observed for some trimers, that we have roughly calculated.