Many species of bacteria communicate and coordinate group behaviors, including toxin production and surface fouling, through a process known as quorum sensing (QS). In Gram-negative bacteria, QS is regulated by <i>N</i>-acyl L-homoserine lactones (AHLs) that possess a polar homoserine lactone head group and a nonpolar aliphatic tail. Past studies demonstrate that AHLs can aggregate in water or adsorb at interfaces, suggesting that molecular self-assembly could play a role in processes that govern bacterial communication. We used a combination of biophysical characterization and atomistic molecular dynamics (MD) simulations to characterize the self-assembly behaviors of 12 structurally-related AHLs. We used static light scattering and measurements of surface tension to determine that four natural AHLs (3-oxo-C8-AHL, 3-oxo-C12-AHL, C12-AHL, and C16-AHL) self-assemble in aqueous media and characterize their critical aggregation concentrations (CACs). Unbiased atomistic MD simulations demonstrated that 3-oxo-C12-AHL can self-assemble into spherical, cylindrical, or bilayer-like aggregates depending on the initial concentration of AHL molecules added to the system; alchemical free energy calculations were then used to predict thermodynamically preferred aggregate structures. Those calculations predicted that AHLs with 10 or 12 tail carbon atoms should form spherical micelles, and that AHLs with 14 or 16 tail carbon atoms should form vesicles in solution. Characterization of solutions of AHLs using transmission electron microscopy (TEM) revealed aggregates with sizes consistent with spherical micelles or small unilamellar vesicles for 3-oxo-C12-AHL and C12-AHL, and the formation of large vesicles (~250 nm) in solutions of C16-AHL. These experimental findings are in general agreement with our simulation predictions. When combined, our results provide new physical insight into the aggregation behavior of this important class of non-ionic amphiphile and suggest that aggregation could potentially play a role in mediating processes that enable bacteria to communicate.

Self-assembly of bacterial quorum sensing signals in aqueous media: Integrated experimental and molecular dynamics study

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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