Modeling the Effect of Hydrophobicity on the Passive Permeation of Solutes across a Bacterial Model Membrane

Passive diffusion across biomembranes is an important
mechanism
of permeation for multiple drugs, including antibiotics. However,
this process is frequently neglected while studying drug uptake and,
in our view, warrants further investigation. Here, we apply molecular
dynamics simulations to investigate the impact of changes in molecular
hydrophobicity on the permeability of a series of inhibitors of the
quorum sensing of Pseudomonas aeruginosa, previously discovered by us, across a membrane model. Overall,
we show that permeation across this membrane model does not correlate
with the molecule’s hydrophobicity. We demonstrate that using
a simple model for permeation, based on the difference between the
maximum and minimum of the free energy profile, outperforms the inhomogeneous
solubility-diffusion model, yielding a permeability ranking that better
agrees with the experimental results, especially for hydrophobic permeants.
The calculated differences in permeability could not explain differences
in in bacterio activity. Nevertheless, substantial
differences in molecular orientation along the permeation pathway
correlate with the in bacterio activity, emphasizing
the importance of analyzing, at an atomistic level, the permeation
pathway of these solutes.