Predicting the\nAntifungal Activity of Small Organic\nCompounds on Aspergillus niger Mold\nusing Molecular Dynamics Simulations

Atomistic models of the plasma membrane of the pathogenic\nmold Aspergillus niger are developed.\nThese models are\ndescribed with an empirical molecular mechanical (MM) force field\nin combination with molecular dynamics (MD) simulations. The solvated\nplasma membrane models are brought into contact with 35 small organic\ncompounds to observe their impact on a variety of membrane properties.\nAll compounds are added at a constant total mass of 1% of the membrane\nmass. In addition, the ability of these compounds to inhibit the pathogenic\ncell growth of mold has been measured. Diffusion of compounds into\nthe membrane model is readily observed during MD simulations. Changes\nin membrane properties found in simulations are not found to correlate\nwith measured antifungal activities of compounds, suggesting that\nMD simulations of up to 1 μs are not sufficiently long to adequately\ndescribe compound-induced membrane disruption. However, properties\nrelated to the position and orientation of compounds relative to the\nmembrane surface as well as hydrogen bonds formed between the compounds\nand the membrane show clear trends that correlate well with measured\nactivities. A combination of these properties enables an activity\nprediction of compounds in good agreement with measurements. Activity\nis found predominantly for compounds that can be decomposed into a\nsingle continuous hydrophobic and hydrophilic moiety. Such active\ncompounds can be energetically inserted most favorably into the membrane.\nThese insertions destabilize the membrane by disrupting the internal\nmembrane hydrogen bond network and by sliding between neighboring\nlipids, thereby separating them.