Professor Patrick Trouillas
Fundamental Physical Chemistry for Biological Applications
Limoges University
Limoges, France

Monday, March 12, 2018
3:00 pm (CT)
3269 Beckman Institute

Abstract

Membrane crossing by xenobiotics (e.g. polyphenol-antioxidants, antivirals, immunosuppressants) is a key pharmacological step. According to their chemical structure, they interact with and anchor to the polar head group region of the bilayers. According to the depth of penetration they can either directly achieve their biological activity (e.g., antioxidant action), or be taken over by membrane metabolizing enzyme (e.g., CYP450). Once inserted in lipid bilayers, some derivatives, as polyphenols, can also form transient noncovalent small aggregates, which may modify their activities. Again, according to their chemical structure, xenobiotics can cross membranes. Although passive permeation can be relatively slow, or virtually impossible for certain derivatives, they can alternatively be taken over by membrane transporters, e.g., solute carrier or ATP- binding transporters (SLC or ABC, respectively). Based on molecular modeling simulations, agreeing with and supporting experimental data, we will provide an overview of xenobiotics-membrane interactions, partitioning and crossing. Special attention will be paid to xenobiotics transport through ABC transporters, which requires large conformational changes from Inward-Facing (IF) to Outward- Facing (OF) conformers. This pumping motion is far beyond the reach of classical molecular dynamics (MD) simulations and to be explored, and it requires the use of biased MD simulations. Using metadynamics parameterized with a series of collective variables, we have studied the energetic landscape of the large conformational changes associated with the drug transport through a prototypical ABC transporter (ABCB1/P-gp) surrounding by a lipid bilayer. Several intermediate conformers were identified, allowing construction of the preferred path from the IF to OF conformers. The IF-occluded conformers, where all domains are in close contact, was thoroughly analyzed to understand how this triggers domain swapping responsible for drug transport. Focus has then been given to the human ABCC4/MRP4 exporter and related polymorphisms (e.g. p.Gly187Trp) due to their clinical impact on membrane transport of a broad range of xenobiotics. MRP4 is expressed at key locations for drug disposition or effects such as in the liver, the kidney and blood cells. So far, no human MRP4 structure has been elucidated, precluding rationalization of its dysfunction at a molecular level. We constructed an atomistic model of the wild type (WT) MRP4 and the p.Gly187Trp variant embedded in different lipid bilayers. Affiliations: 1- INSERM U1248, Limoges University, Fac. Pharmacy, 2 rue du Dr Marcland, 87025 Limoges, France 2- RCPTM, Fac. Sciences, Palacký University, Olomouc, Czech Republic