Predicting the Antifungal Activity of Small Organic Compounds on <i>Aspergillus niger</i> Mold using Molecular Dynamics Simulations

Atomistic models of the plasma membrane of the pathogenic mold <i>Aspergillus niger</i> are developed. These models are described with an empirical molecular mechanical (MM) force field in combination with molecular dynamics (MD) simulations. The solvated plasma membrane models are brought into contact with 35 small organic compounds to observe their impact on a variety of membrane properties. All compounds are added at a constant total mass of 1% of the membrane mass. In addition, the ability of these compounds to inhibit the pathogenic cell growth of mold has been measured. Diffusion of compounds into the membrane model is readily observed during MD simulations. Changes in membrane properties found in simulations are not found to correlate with measured antifungal activities of compounds, suggesting that MD simulations of up to 1 μs are not sufficiently long to adequately describe compound-induced membrane disruption. However, properties related to the position and orientation of compounds relative to the membrane surface as well as hydrogen bonds formed between the compounds and the membrane show clear trends that correlate well with measured activities. A combination of these properties enables an activity prediction of compounds in good agreement with measurements. Activity is found predominantly for compounds that can be decomposed into a single continuous hydrophobic and hydrophilic moiety. Such active compounds can be energetically inserted most favorably into the membrane. These insertions destabilize the membrane by disrupting the internal membrane hydrogen bond network and by sliding between neighboring lipids, thereby separating them.