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University of Cagliari Project – Silvia Acosta Gutierrez

Pathaway Modeling

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Fellow: Silvia Acosta Gutiérrez

Supervisor: Matteo Ceccarelli (University of Cagliari)

 Co-supervisors: Ulrich Kleinekathöfer (Jacobs University)

silviaOur activity focuses on the permeability of antibiotics through general channels, namely OmpF/OmpC from E.coli and MOMP from C.jejuni (collaboration with Aix-Marseille Université, Jacobs University and Saint Andrews University). For the former we have several data available and in particular X-ray co-complex structures with penicillins that we aim to compare with our modelling results. We started characterizing the internal electrostatic of pores looking at the ordering of water molecules, being the latter a natural probe for quantifying an internal electric field because of their dipole.

The group combined MD simulations with an acceleration scheme to follow the translocation of antibiotics through porins at atomic scale. Multi-scale algorithms extend the simulation time to the range of microseconds to milliseconds, making it possible to obtain the reactive pathway that antibiotics follow during passive diffusion. Accelerated MD simulations have revealed a putative translocation pathway for penicillins and fluoroquinolones through OmpF and porins extracted from resistant strains. Through the associated free energy surface (FES) of this process, affinity sites and activation barriers can be identified.

Starting from the X-ray structures obtained by USTAN, we simulated MOMP, both the monomeric and trimeric form, embedded in a phospholipid bilayer. Also from our modelling the two forms do not differ, therefore we used the small monomeric form to investigate the diffusion of ciprofloxacin.

We developed an analysis method to evaluate the internal electric field of pores. Using spheres of water molecules and the Clausius-Mossotti formula, we were able to correlate the ordering of water dipole moment to the internal electric field inside OmpF/OmpC and mutants from clinical strains. These channels show a very strong transversal component of electric field that can change orientation along the axis of the pore.

We quantified the interactions of a few penicillins within OmpF and we compared our free energy minima structure with the X-ray soaked complex structures solved by B. Roux, obtaining a very good agreement. From the one-dimensional free energy surface knowledge we are developing a method to evaluate the flux of molecules traversing the channel upon application of a concentration gradient.

Publications:

Ferrara LG, Wallat GD, Moynié L, Dhanasekar NN, Aliouane S, Acosta-Gutiérrez S, Pagès JM, Bolla JM, Winterhalter M, Ceccarelli M, Naismith JH, J Mol Biol. 428(22): 4528-4543 (2016). doi: 10.1016/j.jmb.2016.09.021.
Scorciapino MA, D’Agostino T, Acosta-Gutiérrez S, Malloci G, Bodrenko I, Ceccarelli M, Future Med Chem. 8(10): 1047-62 (2016). doi: 10.4155/fmc-2016-0038.
Acosta Gutiérrez S, Bodrenko I, Scorciapino MA, Ceccarelli M, Phys Chem Chem Phys. 18(13): 8855-64 (2016). doi: 10.1039/c5cp07902k.