Molecular simulations can help understand the permeation properties of antibiotics through porin channels; methodology and proof of concept
Eric Hajjar, Amit Kumar, Enrico Spiga, Francesca Collu, Paolo Ruggerone and Matteo Ceccarelli
Department of Physics , University of Cagliari . Italy .
Bacterial strains can modulate their susceptibility to antibiotics by under-expressing or mutating protein channels (such as OmpF and OmpC) that populate their outer-membranes. The increased resistance of bacteria calls for a new way to develop antibiotics with a bottom-up approach, i.e. designing molecule with improved properties starting from the knowledge of the molecular mechanisms that control resistance. In this rational drug-design scenario, molecular simulations can have an important role. Indeed, major advances in computing power and scientific algorithm allows for more accurate simulation of larger systems and longer time scales.
In our group, we were able to apply various computational methods such as accelerated MD simulations to follow the paradigm for designing better antibiotics.
First, an introduction to biomolecular simulations will be given. Further, we will see how simulations can be useful to study the transport properties of various antibiotics through porins OmpF and OmpC.
As a proof of concept, the diffusion of a common antibiotic, ampicillin, through the outer membrane porin F (OmpF) was analyzed.The porin was studied as a wild type (WT) and variants with substitutions of key residues at the constriction region, the narrowest part of OmpF. Among the different mutants, a mutation on the residue D113 (altering the charge and/or stericity) affect drastically the Ampicillin translocation and the binding mode of the antibiotic to partners in OmpF; all in all then antibiotic seem to cross faster the constriction zone and this relates to different strength and localization of minima on the associated free energy map. Led by these results, we analyzed an antibiotic that potentially interact less with this residue, such as penicillin-G, which lacks the Ampicillin positive group. Moreover, we further extended this proof of concept to other antibiotics molecules, such as Cephalosporins which are among the most frequently prescribed class of antibiotics.
The simulations results were confronted with experiments, with collaborations with our partners from Bremen, Porto, Marseille and Basilea Pharmaceutica.
A particular emphasis will be put on summing up the strategies and perspectives.
This study demonstrates how theory and experiments can be combined to reveal the mechanism of antibiotic diffusion. Further, this would benefits to the design of new antibiotics with improved transport properties.