P-glycoprotein (P-gp) is an ABC transporter able to export a wide range of chemically diverse molecules out of the cell and is one of primary causes of multidrug resistance in cancer cells. Hence, a better understanding of this transporter is of great importance, but despite admirable scientific efforts, there are still many open questions regarding the function and mechanism of P-gp. For example, the coupling of the ATP hydrolysis to the necessary conformational changes in the protein that would allow cytoplasmic substrate uptake and its extracellular release remains obscure. The physical location of the substrate binding sites of this highly promiscuous protein is another unresolved issue. Significant advances were achieved in the recent years by solving several crystal structures of P-gp and its homologs, effectively capturing the putative initial (inward-open) and final states (outward-open) of the transport process.
The available crystal structures, albeit at rather low resolutions, have opened the door for molecular modelling to examine some of these issues at atomistic level. We used the mouse P-gp structures1,2 as a basis for our computational studies using MD simulations to investigate the stability of the apo form in POPC/cholesterol bilayer.3The P-gp structure exhibits great flexibility, allowing it to adopt a range of metastable conformations that may play a key role in the functional modulation of the transporter upon ATP and substrate binding.