title: Understanding the accumulation of P-glycoprotein substrates within cells: The effect of cholesterol on membrane partitioning.
abstract: The apparent activity of the multidrug transporter P-glycoprotein (P-gp) is enhanced by the presence of cholesterol. Whether this is due to the direct effect of cholesterol on the activity of P-gp, its effect on the local concentration of substrate in the membrane, or its effect on the rate of entry of the drug into the cell, is unknown. In this study, molecular dynamics simulation techniques coupled with potential of mean force calculations have been used to investigate the role of cholesterol in the movement of four P-gp substrates across a POPC bilayer in the presence or absence of 10% cholesterol. The simulations suggest that the presence of cholesterol lowers the free energy associated with entering the middle of the bilayer in a substrate-specific manner. These findings suggest that P-gp substrates may preferentially accumulate in cholesterol-rich regions of the membrane, which may explain its enhanced transport activity.
authors.affiliation: School of Chemistry and Molecular Biosciences (SCMB), University of Queensland, Brisbane, QLD 4072, Australia; Research School of Chemistry (RSC), The Australian National University, Canberra, ACT 2601, Australia.
authors.forename: Nandhitha
authors.initials: N
authors.lastname: Subramanian
authors.affiliation: School of Chemistry and Molecular Biosciences (SCMB), University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schumann-Gillett
authors.affiliation: School of Chemistry and Molecular Biosciences (SCMB), University of Queensland, Brisbane, QLD 4072, Australia; The Institute for Molecular Biosciences (IMB), University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Mark
authors.affiliation: School of Chemistry and Molecular Biosciences (SCMB), University of Queensland, Brisbane, QLD 4072, Australia; Research School of Chemistry (RSC), The Australian National University, Canberra, ACT 2601, Australia. Electronic address: megan.o'mara@anu.edu.au.
authors.forename: Megan L
authors.initials: ML
authors.lastname: O'Mara
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D006801:Humans; D056004:Molecular Dynamics Simulation; D013379:Substrate Specificity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002784:Cholesterol
keywords: Cholesterol; Drug partitioning; Membrane composition; Multidrug resistance; P-glycoprotein; Potential of mean force