Transport through bacterial membrane pores: insights from enhanced sampling simulations

Abstract

Channels in the outer membrane of Gram-negative bacteria provide essential pathways for the controlled and unidirectional transport of ions, nutrients and metabolites into the cell. At the same time, the outer membrane serves as a physical barrier for the penetration of noxious substances such as antibiotics into the bacteria. In this contribution the simulation of ion and substrate transport across such bacterial channels will be detailed. As examples, the translocations of the antibiotics fosfomycin, ciprofloxacin and enrofloxacin through the major diffusion channels OmpF and OmpC have recently been computed using metadynamics and the temperature-accelerated sliced sampling approach (Chem. Rev. 121, 5158 (2021); J. Chem. Theory Comput. 17, 4564 (2021); J. Chem. Theory Comput. 17, 549 (2021)). The results will be compared to experimental findings when possible. A main focus of this contribution is on the testing and application of enhanced sampling approaches, their effective sampling and the inclusion of an enlarged number of degrees of freedom.