Gram-negative bacteria are protected against external attack by an outer membrane. However, general diffusion porins located in this membrane allow the entry, by simple diffusion, of small molecules and, among them, antibiotics (beta-lactams and fluoroquinolones). Strains of bacteria resistant to beta-lactams have shown either a low porin density in the outer membrane, or some mutations at the level of porins affecting their internal size. Understand how antibiotics diffuse through these porins can help researcher to develop new antibiotics with an improved penetration especially when resistance becomes a serious problem for infectious disease. Recent experimental investigations pointed out how the diffusion of antibiotics through a porin is a molecular-based process: during diffusion the antibiotics interact strongly with the amino acids of the porin. Changing either the charge or the hydrophobicity of antibiotics the interaction strenght with the porin changes as well. Using a recent algorithm able to accelerate all-atom MD simulations, the metadynamics, we were able to follow the diffusion of some different antibiotics through the OmpF porin. Simulations provided a microscopic description of the diffusion process with a clear picture of interactions and at the same time made possible to quantify the process via the evaluation of free energy barriers.
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