Structural and dynamic perspectives on the promiscuous transport activity of P-glycoprotein

•P-gp effluxes >200 substrates from the blood-brain endothelium.•Highly flexible transporter that adopts a variety of conformations.•Molecular basis for structure-function is still unresolved.•Mechanism of substrate binding and interactions unresolved.•We review the role of MD simulations in our understanding of P-gp.

The multidrug transporter P-glycoprotein (P-gp) is expressed in the blood-brain barrier endothelium where it effluxes a range of drug substrates, preventing their accumulation within the brain. P-gp has been studied extensively for 40 years because of its crucial role in the absorption, distribution, metabolism and elimination of a range of pharmaceutical compounds. Despite this, many aspects of the structure-function mechanism of P-gp are unresolved. Here we review the emerging role of molecular dynamics simulation techniques in our understanding of the membrane-embedded conformation of P-gp. We discuss its conformational plasticity in the presence and absence of ATP, and recent efforts to characterize the drug binding sites and uptake pathways.

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