Drug-bacterial membrane interactions: A Tale of two force fields

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), a gram-positive bacteria, is known to infect and kill millions of people worldwide, specifically in poor and developing countries. M.tb has unique characteristics in terms of the presence of an extraordinarily thick cell wall structure, mainly composed of mycolic acid (MA) and arabinogalactan (AG). Between these components, mycolic acid is of particular interest because it exhibits extremely low permeability for most of the drug molecules, thus helping M.tb to survive against medical treatment. Hence, it is extremely useful to study the interactions between drug molecules and mycolic acids in order to better design potential TB medicine. On that premise, the present work aims to computationally model mycolic acid monolayer and probe its permeability against some first-line TB drugs, namely ethambutol, ethionamide, and isoniazid. It is a known fact that such modelling strongly depends on the interaction parameters used. The current study addresses this issue by employing two widely used force fields-GROMOS 54A7-ATB (hereafter GROMOS) united atom force fields and CHARMM36 (hereafter CHARMM) all-atom force fields to collate the drug-mycolic acid interplay. Our findings indicate that both force fields provide consistent results in terms of the mode of drug-monolayer interactions but significantly differ for the monolayer permeability. Mycolic acid monolayer generally exhibited a higher free energy barrier of crossing using CHARMM FF, while GROMOS parameters provide better stability of drug molecules on the monolayer surface, which can be attributed to the greater electrostatic potential at the monolayer-water interface. Both the force field parameters predicted the highest resistance against ethambutol, the most soluble molecule. However, significant differences can be recorded for the other two molecules with the change in the interaction parameter set. In summary, our study provides insight into the dependency of in silico modelling of membranes on force field parameters together with the guidelines to investigate the drug-membrane interactions consisting of non-standard lipids/fatty acids.