Aggregation States Driven by Dipole Interactions Regulates Action Mechanism of Polyene Antibiotics

Abstract

Due to its clinical relevance, the action mechanism of the polyene antibiotic Amphotericin B (AmB) has been studied extensively using both experimental (Venegas-Cotero et al 2003, Kasai et al. 2008) and theoretical (Baginski et al. 2005, Czub et al. 2007) approaches. AmB is currently the drug of choice for treating advanced systemic fungal infections in spite of having a strong collateral toxicity. There is evidence showing that AmB acts at the cellular membrane. However, AmB aggregation could occur in the aqueous solution previous to absorption into the membrane. These aggregation states have been proposed as one of the molecular factors responsible for its action mechanism (Bolard 1991, Szlinder-Richert 2001). The molecular details of this process, in terms of spatial configuration and interaction energy, are poorly understood.In this work, the molecular aggregation mechanism, as a function of AmB concentration in water, was studied through molecular dynamics. Hydrophobic forces, hydrogen bonding and dipole-dipole interactions were characterized. At low concentration not all possible dimer configurations were observed. After running a Potential of Mean Force analysis, one dimer configuration was identified as the most energetically favorable. In this, both molecules are interacting head to tail in an antiparallel fashion. When increasing concentration, the drug still aggregates quickly (within 50 ns), forming higher aggregates. In all aggregation states found, dipole-dipole interactions were identified as the main interacting force. In addition, since AmB is believed to absorb into the membrane, Free energy of solvation in low dielectric media, and the partition coefficient as a function of aggregation state, were calculated. Our results show that AmB aggregates before membrane absorption.