Towards In-Silica Screening of Molecule Permeation through Outer Membrane Channels in Gramm-Negative Bacteria

The demand of new drugs for combating multidrug-resistant bacteria appears more urgent for Gram-negative bacteria: the presence of the outer membrane, which hinders the access of molecules to internal targets, renders the development of anti-infectives more challenging. Today neither a robust screening method for permeation nor defined physical/chemical rules governing permeation through the outer membrane are available. By assuming diffusion as the physical mechanism of the transport of molecules through the channels, we suggest a simple quantitative model for the free energy profile of the molecule-pore interaction. The major penetration barrier has an entropic origin and comes from the steric constraints in the channel. It strongly depends on the average dimension of the pore and that of the molecule as well as on their fluctuations. The macroscopic electrostatic interactions modulate the steric barrier and may either compensate or increase the latter locally. The final tune of the total free energy profile is attributed to the specific interactions like hydrogen bonds, hydrophobic, etc. The diffusional flux of molecules through channels is calculated then with the analytic solution to the Nernst-Planck-type equation provided the chemical potential difference at the sides of the membrane is known. Being based on the clear physical conception, the parameters of the model may be obtained from the all-atom MD simulations for a membrane channel and the molecules separately. Alternatively, the model may be considered as a scoring function for fast quantification of the pore permeability for molecules with the parameters fit to the available experimental data. This, in particular, opens up the possibility for the computational screening of virtual libraries of possible modifications of an antibiotic in order to improve its permeability through the membrane.