TY - JOUR
T1 - Multi-Phase Solvation Model for Biological Membranes
T2 - Molecular Action Mechanism of Amphotericin B
AU - Falcón-González, J. M.
AU - Jiménez-Domínguez, G.
AU - Ortega-Blake, I.
AU - Carrillo-Tripp, M.
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/7/11
Y1 - 2017/7/11
N2 - Amphotericin B (AmB) is still the most effective drug for the treatment of systemic fungal infections in humans. Despite significant theoretical and experimental efforts trying to understand its molecular mechanism of action, the answer has remained elusive. In this work, we present a computational methodology to test the current membrane related hypotheses, namely, transmembrane ion channel, adsorption, and sterol sponge. We use a thermodynamic approach in which we represent the membrane by a multiphase solvation model with atomic detail (MMPSM) and calculate the free energy of transferring the drug between phases with different dielectric properties. Furthermore, we compare AmB to a chemical analogue with increased safety, an l-histidine methyl ester of AmB. Our findings reveal that both drugs dimerize in all solvents studied here. Also, it is energetically unfavorable for the drugs to penetrate into the hydrophobic core of the membrane, unless their concentration is high. Finally, it is thermodynamically possible that the sterols migrate from the membrane into a drug droplet adsorbed at the surface of the bilayer. In light of our results, several effects could take place in the complex antibiotic process. We suggest a molecular mechanism that connects all three hypotheses through a drug concentration dependence and propose that the drug promotes the formation of membrane toroidal pores. Because MMPSM is of general interest, we made it available at http://tripplab.com/tools/mmpsm.
AB - Amphotericin B (AmB) is still the most effective drug for the treatment of systemic fungal infections in humans. Despite significant theoretical and experimental efforts trying to understand its molecular mechanism of action, the answer has remained elusive. In this work, we present a computational methodology to test the current membrane related hypotheses, namely, transmembrane ion channel, adsorption, and sterol sponge. We use a thermodynamic approach in which we represent the membrane by a multiphase solvation model with atomic detail (MMPSM) and calculate the free energy of transferring the drug between phases with different dielectric properties. Furthermore, we compare AmB to a chemical analogue with increased safety, an l-histidine methyl ester of AmB. Our findings reveal that both drugs dimerize in all solvents studied here. Also, it is energetically unfavorable for the drugs to penetrate into the hydrophobic core of the membrane, unless their concentration is high. Finally, it is thermodynamically possible that the sterols migrate from the membrane into a drug droplet adsorbed at the surface of the bilayer. In light of our results, several effects could take place in the complex antibiotic process. We suggest a molecular mechanism that connects all three hypotheses through a drug concentration dependence and propose that the drug promotes the formation of membrane toroidal pores. Because MMPSM is of general interest, we made it available at http://tripplab.com/tools/mmpsm.
UR - http://www.scopus.com/inward/record.url?scp=85027054727&partnerID=8YFLogxK
U2 - 10.1021/acs.jctc.7b00337
DO - 10.1021/acs.jctc.7b00337
M3 - Artículo
C2 - 28553993
AN - SCOPUS:85027054727
SN - 1549-9618
VL - 13
SP - 3388
EP - 3397
JO - Journal of Chemical Theory and Computation
JF - Journal of Chemical Theory and Computation
IS - 7
ER -