Transport Properties in Specific Porins from A. baumannii and Ion Channels.

This work is about the computational study of two cases of ion channel systems; OccAB porins from gram-negative bacterium and human TPC2 channel. In particular, describe the biophysical properties of transport processes in OccAB porins, the TPC2 channel-ligand binding interactions on the basis of molecular modelling approaches. The first part of this thesis focuses on the study of OccAB porins that are ion channels located in the outer membrane of gram-negative pathogen A. baumannii. These channels work as filters to the small molecule and antibiotics translocation through the outer membrane. In order to study, at atomic scale, the parameters that modulate their selectivity to specific substrates, we applied different molecular dynamics simulation methods. In particular, we reported here the surface free energy of the translocation barriers of each channel of OccAB1-4, first, to natural substrates (arginine, glutamic acid and glycine) in order to probe the importance of the molecular charge and size in the discrimination of small molecules. We then evaluated the free energy translocation barriers of fives molecules of antibiotics through OccAB1, the most open channel among OccAB porins. This latter investigation, revealed the crucial role of the internal transversal electric field located in the constriction region of OccAB1 in guiding the translocation of molecules of antibiotics through this channel. Here, we reported a quantification of the electric filed, the free energy surfaces of the translocation barriers and the interactions involved in the molecules-porins complexes. The second part of the thesis, treated the human TPC2 gated sodium ion channel playing an essential role in several cellular functions and signaling regulation. As a result of its involvement in several important diseases such as Parkinson’s disease and Ebola virus, the TPC2 channel has emerged as an important therapeutic target in early drug discovery and development. As part of this thesis, we focused on the study of two molecules, naringenin and verapamil, known to act as blockers in similar gated-ion channels in order to check whether these selected molecules have the same binding sites in the human TPC2 channel, by means of molecular modelling and docking method. Our results give atomistic information about putative binding sites of these potential blockers. We reported the molecular basis and the major modes of binding that can be used as supporting information for mutagenesis experiments for the understanding of the complex mechanism of these channel with two proposed small molecules to act as blockers. Overall, the use of molecular modelling methods for the study of these two membrane systems has contributed to elucidate complex biological processes such as transport through the outer membrane and to describe physical-chemical parameters involved in the formation of the functional complex systems.