Modeling the human p-glycoprotein translocation mechanism using targeted molecular dynamics
Speir, Ethan J.
MetadataShow full item record
P-glycoprotein (P-gp), a member of the ABC-transporter superfamily, is a transmembrane protein that holds clinical importance due to its role in drug metabolism and multi-drug resistance (MDR) in cancer. Because crystallization attempts have failed at elucidating its 3D structure, recent research efforts have focused on constructing homology models of human P-gp. Prior to 2009, these homology models were primarily based upon bacterial transporters such as Sav1866, MalkK, and MsbA that represented the inward-facing conformation of P-gp. Following the release of an inward-facing mouse P-gp-based homology model of human P-gp, however, simulations modeling the inward to outward transition of P-gp have since been made possible. In this study, a targeted molecular dynamic (TMD) simulation is performed in order to model the translocation mechanism of human P-gp. This simulation provides insight into the gating scheme of P-gp itself as well as other ABC-transporters such as the cystic fibrosis transmembrane conductance regulator (CFTR), a protein implicated in the pathophysiology of cystic fibrosis.