The free energy of small solute permeation through the E. coli outer membrane has a distinctly asymmetric profile

Abstract

Permeation of small molecules across cell membranes is a
ubiquitous process in biology and is dependent on the principles of physical
chemistry at the molecular level. Here we use atomistic molecular dynamics
simulations to calculate the free energy of permeation of a range of small
molecules through a model of the outer membrane of Escherichia coli, an
archetypical Gram-negative bacterium. The model membrane contains
lipopolysaccharide (LPS) molecules in the outer leaflet and phospholipids in
the inner leaflet. Our results show that the energetic barriers to permeation
through the two leaflets of the membrane are distinctly asymmetric; the LPS
headgroups provide a less energetically favorable environment for organic
compounds than do phospholipids. In summary, we provide the first
reported estimates of the relative free energies associated with the different
chemical environments experienced by solutes as they attempt to cross the
outer membrane of a Gram-negative bacterium. These results provide key
insights for the development of novel antibiotics that target these bacteria.

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ORCID for Syma Khalid: orcid.org/0000-0002-3694-5044

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