Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives - a molecular dynamics study

Jacek Czub , Anna Neumann , Edward Borowski , Maciej Baginski

Amphotericin B (AmB) is an effective but very toxic antifungal antibiotic. In our laboratory a series of AmB derivatives of improved selectivity of action was synthesized and tested. To understand molecular basis of this improvement, comparative conformational studies of amphotericin B and its two more selective derivatives were carried out in an aqueous solution and in a lipid membrane. These molecular simulation studies revealed that within a membrane environment the conformational behavior of the derivatives differs significantly from the one observed for the parent molecule. Possible reasons for such a difference are analyzed. Furthermore, we hypothesize that the observed conformational transition within the polar head of AmB derivatives may lead to destabilization of antibiotic-induced transmembrane channels. Consequently, the selective toxicity of the derivatives should increase as ergosterol-rich liquid-ordered domains are more rigid and conformationally ordered than their cholesterol-containing counterparts, and as such may better support less stable channel structure.

Mots clés: Amphotericin B; lipid bilayer; molecular dynamics; free energy calculations; conformational analysis

Jacek Czub, Anna Neumann, Edward Borowski, Maciej Baginski. Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives - a molecular dynamics study. Biophysical Chemistry, 2009, 141 (1), pp.105. ⟨10.1016/j.bpc.2009.01.001⟩. ⟨hal-00531140⟩