Silvia successfully defended her PhD at the University of Cagliari (Physics Department) on March the 1st, 2017. Here is a summary.
Permeability in Gram-negative bacteria: A microscopic journey
Bacteria multi-drug resistance is a challenging problem of contemporary medicine and a new molecular framework for antibiotics is needed. General bacterial porins are recognized as the main pathway for polar antibiotics, but the permeability rules are still under debate. Recent works in literature pointed the electrostatics of the channel to be responsible for its filtering mechanism, and some theoretical investigations are already reported in the literature aimed at characterizing the electrostatics inside water-filled channels.
Using Molecular dynamics simulations we revealed the electrostatic filtering mechanism for porins, using water as sensing tool. We further quantify from water polarization density inside the channel the macroscopic internal electric field inside porins. This method allowed us to put forward an ultra-coarse-grained model in which the channel is described by its cross-section area, internal electric field and electrostatic potential along the axis of diffusion. Once these three descriptors are defined, it is possible to estimate the whole free energy along the channel axis of diffusion for a molecule represented by its size, charge and electric dipole moment in a few seconds.
This model would allow to virtually screening libraries of molecules searching for hits with enhanced permeability. These results may have important implications for the formulation of a general model for antibiotics translocation, and can be taken into account for rational drug design.