Self-association of amphotericin B in water.: Theoretical energy and spectroscopy studies

This present work is devoted to the study of the behavior in water of important antifungal drug, the amphiphilic Amphotericin-B (AmB) molecule. Experimental spectroscopy data, namely, the modification of the AmB UV absorption spectrum in water (hypsochromic frequency shift) with the increasing AmB concentration, indicate the self-association of the molecule in water. In this work, a possible three-dimensional structure of the AmB self-associated species present in water has been determined by using in concert both spectroscopy and energy information and not by fitting the calculated: UV absorption spectrum to the experimental one. The calculations have been performed upon AmB dimers and helicoidal oligomers involving 2-8 unit cells. The total energy of any helicoidal oligomer has: been evaluated taking into account, besides the intermolecular interactions (computed using an accurate intermolecular interaction potential), (i) the "thermal" effects evaluated utilizing the well-known formulas of statistical thermodynamics and (ii) "solvent" effects calculated in the framework of an adequate continuum model. It has been shown that all energy results obtained for the different helicoidal oligomers may be extended to infinite helicoidal aggregates. In conclusion, (i) The study of the evolution with Nuc (the number of unit cells) of the total energy (involving all here-above cited terms) of both single and double helices has shown that the highest energy gain (per AmB molecule) is obtained with the double helix. (ii) Such a stabilization mainly proceeds from van der Waals forces together with entropy factors. (iii) This optimized double helix, which is characterized by an helicoidal angle, theta = 30 degrees, and an intercell distance R as 5.7 Angstrom, (thus a pitch of 62.7 Angstrom), leads to an hypsochromic frequency shift (Delta v(+)) calculated as 3950 cm(-1), a value which is quite close to the experimental one, 4368 cm(-1).