Amar Krishna Gopinath

Understanding the translocation of fatty acids through bacterial membrane channels using molecular dynamics

Fatty acids are a class of compounds exhibiting contrasting effects on bacterial growth and viability. Depending on their chemical structure and concentration in the medium, they may serve as feed stock for lipid biosynthesis or act as antimicrobials by cell membrane disruption. A molecular level picture of the interactions of fatty acids with bacterial cell membranes is essential to explain the mechanism of such processes. We have investigated the translocation of lauric acid through proteins named porins which act as channels across the outer membrane of Gram-negative bacteria. To capture insights into the translocation mechanism within the timescale of simulation, an enhanced sampling technique named umbrella sampling was utilized. Subsequently, from the sampled trajectories, a free energy profile along the z coordinate of translocation was constructed, which would describe the energetic barriers experienced by the molecule as it would cross through the porin. The loop L3, which forms a constriction at the middle of the porin is observed to pose a physical barrier for translocation. This barrier is amplified by the presence of cationic binding spots on either side of the loop, which trap the anionic fatty acid. Hence, it is energetically favorable for the fatty acid to enter the channel, but faces a physical barrier posed by loop L3 to completely cross the same. Comparison of free energy of translocation, estimated similarly for different fatty acids, would enable the identification of structural features that enable or disable translocation.