The essential cellular functions of the mitochondrion require the exchange of a wide variety of molecules across its two membranes, which is carried out by different membrane proteins.The Voltage-Dependent Anion Channel (VDAC) located in the mitochondrial outer membrane (MOM) is responsible for the passage of various ions and small molecules to and from the intermembrane space. It is also involved in the regulation of cellular processes through its interactions with lipids or other proteins.At the MOM level, we studied the transport, through VDAC, of small inorganic ions and of thiamine pyrophosphate (TPP), an essential cofactor. Using different simulation methods such as Brownian dynamics (BD), All-Atom (AA) molecular dynamics (MD) and Coarse-Grained (CG) MD, we investigated the effect of two factors on the regulation of VDAC ion selectivity: ionic strength and membrane lipid composition. All simulation types show that VDAC becomes less selective towards anions with increasing salt concentration. The simulations further suggest that the selectivity mechanism occurs due to the filtering of some basic residues that point into the pore lumen. Furthermore, MD simulations show that the lipid composition of the membrane modulates the distribution of ions inside VDAC. In a comparison of POPE versus POPC bilayer, this regulation occurs through the more persistent interactions of some acidic residues located on both edges of the β-barrel with POPE head groups which, in turn, alters the electrostatic potential in the lumen which consequently affects the pore selectivity. CG MD simulations show that this mechanism also occurs in a mixed POPE/POPC bilayer by an enrichment of POPE on VDAC surface.In order to simulate the transport of the TPP, force field parameters have been developed and validated. Simulations of the translocation of TPP through VDAC show analogies with the mechanism used by other previously studied metabolites, in particular with ATP. At the mitochondrial inner membrane level, the mechanism of TPP transport by the specific thiamine pyrophosphate transporter (TPPT) shows significant similarities with the mechanism proposed for other members of the mitochondrial carrier family to which TPPT belongs. They mainly are the energetics arising from the alternating formation and disruption of two salt bridge networks, one on the matrix side and the other on the cytosolic side, and the interactions, of an ionic nature, formed by TPP during its binding in TPPT central cavity. Furthermore, the energy contribution provided by the cytosolic network establishes a weaker barrier than that of the matrix network, which may support the hypothesis of a uniport activity of TPPT. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished
| Identifer | oai:union.ndltd.org:ulb.ac.be/oai:dipot.ulb.ac.be:2013/331176 |
| Date | 07 September 2021 |
| Creators | Van Liefferinge, François |
| Contributors | Prévost, Martine, Goormaghtigh, Erik, Gilis, Dimitri, Wintjens, René, Michaux, Catherine, Becker, Jean-Paul |
| Publisher | Universite Libre de Bruxelles, Université libre de Bruxelles, Faculté des Sciences – Chimie, Bruxelles |
| Source Sets | Université libre de Bruxelles |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:ulb-repo/semantics/doctoralThesis, info:ulb-repo/semantics/openurl/vlink-dissertation |
| Format | 3 full-text file(s): application/pdf | application/pdf | application/pdf |
| Rights | 3 full-text file(s): info:eu-repo/semantics/closedAccess | info:eu-repo/semantics/restrictedAccess | info:eu-repo/semantics/openAccess |
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