The use of peptides as antibacterial drugs is sometimes limited since most peptides show low cell permeability and can be easily degraded by proteases. In contrast, peptoids, a synthetic mimic of peptides, show a resistance towards enzymatic degradation and carry a higher cell permeability. Therefore, peptoids as antibacterial drugs and especially their interactions with membranes are an important in the field of drug development.<br/>We study the interactions of a variety of lipid like peptoids to lipid membranes which are shown experimentally to exhibit antibacterial activity. Using computational techniques such as umbrella sampling and parallel bias metadynamics (PBMetaD) we elucidated possible mechanisms for their antibacterial activity. Small variations in the peptoid sequence are shown to change the free energy associated with the insertion into a lipid membrane by over 20 kcal/mol. Changes on the order of 10 kcal/mol are also observed for variations in the membrane composition for a single sequence, highlighting the specificity of membrane--peptoid interactions.<br/>PBMetaD simulations performed for higher concentrations of charged peptoids starting from solution, reveals the formation of an initial pore like structure in a POPC lipid membrane. As such pore formation in a bacterial membrane could create a channel within a bacterial cell, this is considered a potential mechanism for the antibacterial activity of these peptoids.

Molecular dynamics study of peptoid-membrane interactions and potential pore-formation

ACS Spring 2022

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