In silico investigation of xenobiotic interactions with lipid bilayers and ABC membrane transporters, the case of ABCC4/MRP4

Abstract : Understanding the biological mechanisms of action of membrane proteins requires the comprehension of the interactions of xenobiotics with these proteins and with lipid membranes. Experimental methods are often demanding and only partially respond to xenobiotic-membrane-protein interactions. In silico molecular modeling is a serious alternative to tackle these issues. Molecular dynamics (MD) and biased dynamics simulations have opened many perspectives by providing an atomistic description of these intermolecular interactions. Using MD simulations, we built a model of the human ABC ABCC4/MRP4 transporter. We explored the influence of cholesterol on this protein as well as the impact of a polymorphism known to shut down the transport activity of this protein. We also studied the interaction of xenobiotics with this human transporter. The transport cycle of the ABC transporters was investigated in an attempt to better understand how it works.Interactions between lipid membranes and xenobiotics were explored by examining their ability to incorporate lipid membranes. Lipid mixtures with cholesterol showed a significant impact on the human protein ABCC4/MRP4 and on the xenobiotics studied. The importance of regions, domains constituting the ABCC4/MRP4 protein as well as the importance of specific residues has been clearly demonstrated. We also observed intermediates in the transport cycle of an ABC transporter in conjunction with structural changes occurring during this cycle.
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Benjamin Chantemargue. In silico investigation of xenobiotic interactions with lipid bilayers and ABC membrane transporters, the case of ABCC4/MRP4. Human health and pathology. Université de Limoges; Univerzita Palackého (Olomouc, République tchèque), 2018. English. ⟨NNT : 2018LIMO0077⟩. ⟨tel-02418604⟩

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