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Biophys. J. BioFAST: First Published March 24, 2006. doi:10.1529/biophysj.105.077743
© 2006 by the Biophysical Society.

A more recent version of this article appeared on June 1, 2006.
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MEMBRANES

Interaction of transported drugs with the lipid bilayer and P-glycoprotein through a solvation exchange mechanism

Hiroshi Omote 1 and Marwan K. Al-Shawi 2*

1 University of Virginia
2 Univ Virginia

* To whom correspondence should be addressed. E-mail: ma9a{at}virginia.edu.

Submitted on November 14, 2005
Revised on December 14, 2005
Accepted on 4 January 2006


  Abstract
Broad substrate specificity of human P-glycoprotein (ABCB1) is an essential feature of multidrug resistance. Transport substrates of P-glycoprotein are mostly hydrophobic and many of them have net positive charge. These compounds partition into the membrane. Utilizing the energy of ATP hydrolysis, P-glycoprotein is thought to take up substrates from the cytoplasmic leaflet of the plasma membrane and to transport them to the outside of the cell. We examined this model by molecular dynamics simulation of the lipid bilayer, in the presence of transport substrates together with an atomic resolution structural model of P-glycoprotein. Taken together with previous EPR studies, the results suggest that most transported drugs are concentrated near the surface zone of the inner leaflet of the plasma membrane. Here the drugs can easily diffuse laterally into the drug-binding site of P-glycoprotein through an open cleft. It was concluded that the initial high-affinity drug-binding site was located in the interfacial surface area of P-glycoprotein in contact with the membrane interface. Based on these results and our recent kinetic studies, a "solvation exchange" drug transport mechanism of P-glycoprotein is discussed. A molecular basis for the improved colchicine transport efficiency by the much-studied colchicine-resistance G185V mutant human P-glycoprotein is also provided.

Key Words: Energy coupling, Molecular dynamics, Molecular modelling, Multidrug resistance, Structure and function, Transport mechanism




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Copyright © 2006 by the Biophysical Society.