Molecular dynamics studies of P-glycoprotein

• Main Author: Domicevica, Laura
• Other Authors: Biggin, Philip
• Published: University of Oxford 2016
• Subjects: 572
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.730424

Due to its involvement in multidrug resistance in cancer and other disorders, P-glycoprotein has been a subject of many studies, however, the evidence from structural and functional investigations is often conflicting. Homology models of human P-glycoprotein were prepared and analysed to choose the most suitable model for further experiments. Molecular dynamics simulations of the homology models revealed closure of potential substrate entrance gates. The results of the steered molecular dynamics and other simulations suggest that amitriptyline enters the central cavity through the cytoplasmic part of the entrance gates formed by transmembrane helices 4 and 6. P-glycoprotein was inserted in a complex asymmetric bilayer designed to mimic the composition of blood-brain barrier and the system was subjected to coarse-grained simulations and more interesting cases were converted to atomistic resolution. Three major insights were obtained. Firstly, P-glycoprotein affects the local bilayer environment by causing local ordering of lipids and decrease in lipid diffusion constants. Secondly, several potential cholesterol binding sites were observed in the simulations. Lastly, the presence of complex bilayer might affect the exibility of substrate entrance gate-forming helices. Taken together, these results highlight the importance of structural studies that can generate new and testable hypotheses.