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Molecular Dynamics Simulations of E. coli MsbA Transmembrane Domain: Formation of a Semipore Structure

Service de Biophysique des Fonctions Membranaires, Département de Biologie Joliot-Curie and URA 2096 CNRS, Direction des Sciences du Vivant/Commissariat á l'Energie Atomique (CEA), Centre de Saclay, 91191 Gif-sur-Yvette cedex, France

Correspondence: Address reprint requests to Dr. Stéphane Orlowski, SBFM/DBJC and URA 2096 CNRS, CEA Saclay, 91191 Gif-sur-Yvette cedex, France. Tel.: 33-1-69-08-95-77; Fax: 33-1-69-08-81-39; E-mail: orlowski{at}dsvidf.cea.fr.

The human P-glycoprotein (MDR1/P-gp) is an ATP-binding cassette (ABC) transporter involved in cellular response to chemical stress and failures of anticancer chemotherapy. In the absence of a high-resolution structure for P-gp, we were interested in the closest P-gp homolog for which a crystal structure is available: the bacterial ABC transporter MsbA. Here we present the molecular dynamics simulations performed on the transmembrane domain of the open-state MsbA in a bilayer composed of palmitoyl oleoyl phosphatidylethanolamine lipids. The system studied contained more than 90,000 atoms and was simulated for 50 ns. This simulation shows that the open-state structure of MsbA can be stable in a membrane environment and provides invaluable insights into the structural relationships between the protein and its surrounding lipids. This study reveals the formation of a semipore-like structure stabilized by two key phospholipids which interact with the hinge region of the protein during the entire simulation. Multiple sequence alignments of ABC transporters reveal that one of the residues involved in the interaction with these two phospholipids are under a strong selection pressure specifically applied on the bacterial homologs of MsbA. Hence, comparison of molecular dynamics simulation and phylogenetic data appears as a powerful approach to investigate the functional relevance of molecular events occurring during simulations.