Molecular dynamics simulations of E coli MsbA transmembrane domain : formation of a semi-pore structure
David Y HAUBERTIN 1, Hocine MADAOUI 1, Alain SANSON 1, Raphaël GUEROIS 1 and Stéphane ORLOWSKI 1*
1 CEA
* To whom correspondence should be addressed. E-mail: orlowski{at}dsvidf.cea.fr.
Submitted on February 24, 2006
Revised on March 20, 2006
Accepted on 31 May 2006
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Abstract |
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The human P-glycoprotein (MDR1/P-gp) is an 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 homologue 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 POPE lipids. The system studied contained more than 90,000 atoms and was simulated for 50ns. This simulation shows that the open-state structure of MsbA can be stable in a membrane environment and provides precious insights into the structural relationships between the protein and its surrounding lipids. This study reveals the formation of a semi-pore 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 homologues of MsbA. Hence, comparison of molecular dynamics simulation and phylogenetic data appears as a powerful approach to investigate the functional relevance of molecular events occuring during simulations.
Key Words:
ABC transporters, MsbA, P-glycoprotein, lipid translocation, molecular dynamics, protein-lipid interaction
