Catalytic transitions in the MDR1 P‐glycoprotein probed by target molecular dynamics

Abstract

A serious problem for cancer and viral chemotherapies is the active efflux of drugs catalyzed by ABC‐transporters. Human P‐glycoprotein (Pgp), one such problematic transporter, is a transmembrane protein composed of two nucleotide binding domains (NBD) and two transmembrane domains (TMD) in a NBD1‐TMD1‐NBD2‐TMD2 topology. Two ATP binding sites are created from both NBDs and drug binding sites (DBS) are created from both TMDs. It is thought that binding of ATP engages the two NBDs and hydrolysis leads to a repositioning of the DBS from inward facing to outward facing conformations, but the details of these complex conformational changes remain unknown. Targeted molecular dynamics (MD) techniques enable the sampling of large conformational changes in a protein that would normally be inaccessible due to large energy barriers. In this work, targeted MD of Pgp using 4 target structures was performed starting with fully disengaged NBDs and inward facing DBS and ending with fully engaged NBDs with fully opened outward DBS. 26 nonredundant transitional protein structures were identified by statistical methods and drug docking of 23 drugs was tested on each structure. Previous biochemical studies strongly support the results obtained here. The combination of protein dynamics and dynamic ligand docking used here revealed new details of the Pgp transport mechanism. Supported by NIH 1R15GM094771‐01A1 to P.D. Vogel and JGW.