Filtering with Electric Field: The Case of E. coli Porins.
Although the role of general bacterial porins is well established as main pathway for polar antibiotics, the molecular details of their mode-of-action are still under debate. Using molecular dynamics simulations and water as a probe, we demonstrated the strong ordering of water molecules, differently tuned along the axis of diffusion in the transversal direction. Preserved features and important differences were characterized for different channels, allowing to put forward a general model for molecular filtering. The intrinsic electric field, responsible for water ordering, (i) filters those dipolar molecules that can compensate the entropy decrease by dipole alignment in the restricted region and (ii) might create an additional barrier by changing direction when escaping from the restricted region. We tested this model using two antibiotics, cefepime and cefotaxime, through metadynamics free energy calculations. A rational drug design should take this into account for screening molecules with improved permeation properties.
†Department of Physics, University of Cagliari, Cittadella Universitaria di Monserrato, S.P.8-km 0.700, 09042 Monserrato, Cagliari, Italy.
Silvia
S
Acosta-Gutierrez
‡Department of Biomedical Sciences, Biochemistry Unit, University of Cagliari, Cittadella Universitaria di Monserrato, S.P.8-km 0.700, 09042 Monserrato, Cagliari, Italy.
Mariano Andrea
MA
Scorciapino
†Department of Physics, University of Cagliari, Cittadella Universitaria di Monserrato, S.P.8-km 0.700, 09042 Monserrato, Cagliari, Italy.
Igor
I
Bodrenko
†Department of Physics, University of Cagliari, Cittadella Universitaria di Monserrato, S.P.8-km 0.700, 09042 Monserrato, Cagliari, Italy.
Matteo
M
Ceccarelli
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D000077723:Cefepime; D002439:Cefotaxime / Q000737:chemistry / Q000378:metabolism; D002511:Cephalosporins / Q000737:chemistry / Q000378:metabolism; D004560:Electricity; D004926:Escherichia coli / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D018272:Porins / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D018272:Porins; D014867:Water; D000077723:Cefepime; D002439:Cefotaxime
Water; antibiotics; bacterial resistance; molecular dynamics simulations; passive diffusion; protein channels; rational drug design