The flexibility of P-glycoprotein for its poly-specific drug binding from molecular dynamics simulations.
The multidrug efflux pump P-glycoprotein (P-gp) contributes to multidrug resistance in about half of human cancers. Recently, high resolution X-ray crystal structures of mouse P-gp (inward-facing) were reported, which significantly facilitates the understanding of the function of P-gp and the structure-based design of inhibitors for P-gp. Here we perform 20 ns molecular dynamics simulations of inward-facing P-gp with/without ligand in explicit lipid and water to investigate the flexibility of P-gp for its poly-specific drug binding. By analyzing the interactions between P-gp and QZ59-RRR or QZ59-SSS, we summarize the important residues and the flexibility of different parts of P-gp. Particularly, the flexibility of the side chains of aromatic residues (Phe and Tyr) allows them to form rotamers with different orientations in the binding pocket, which plays a critical role for the poly-specificity of the drug-binding cavity of P-gp. MD simulations reveal that trans-membrane (TM) TM12 and TM6 are flexible and contribute to the poly-specific drug binding, while TM4 and TM5 are rigid and stabilize the whole structure. We also construct outward-facing P-gp based on the MsbA structure and perform 20 ns MD simulations. The comparison between the MD results for outward-facing P-gp and those for inward-facing P-gp shows that the TM parts in outward-facing P-gp undergo significant conformational change to facilitate the export of small molecules.
Institute of Functional Nano & Soft Materials and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, 215123, PR China.
Ming
M
Liu
Tingjun
T
Hou
Zhiwei
Z
Feng
Youyong
Y
Li
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D018432:Drug Resistance, Multiple; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D016415:Sequence Alignment
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008024:Ligands; D010456:Peptides, Cyclic; C539646:cyclic-tris-(R)-valineselenazole