The Mechanism Of P-glycoprotein For Its Polyspecific Drug Binding From Molecular Dynamics

The ABC (ATP-binding cassette) transport protein family is a large class oftransmembrane proteins, its main function is to use ATP hydrolysis energy that put thesubstrates binding with it out of the cells. The ABC transporter superfamily containsmore than100kinds of membrane transport proteins, and widely present in a variouscells of bacteria, plants and mammals, the key features include that the output of thetoxic substances, intake of nutritional substances, ions, peptides, and cellular signaltransfer, etc. The multidrug efflux pump P-glycoprotein (P-gp) contributes to multidrugresistance in about half of human cancers. Recently, high resolution X-ray crystalstructures of mouse P-gp (inward-facing) were reported, which significantly facilitatesthe understanding of function of P-gp and structure based design of inhibitors for P-gp.Here we use crystal structure of P-gp (inward-facing) and homology structure of P-gp(outward-facing) to perform molecular dynamics and analysis. Our study providesstructural information and mechanism for poly-specific drug binding and structuretransition of Pgp.This thesis is formed by two parts.In the first part, we perform10ns molecular dynamics (MD) of inward-facing P-gpwith/without ligand(QZ59-RRR,QZ59-SSS) in explicit lipid and water environment,after the end of the simulation, We observe the dynamics of these three structures ofP-gp and combined with previous studies, prove that P-gp has the multidrug resistancewas mainly due to its poly-specific binding and the flexibility of its binding pocket, anddiscuss some structural changes and functions of some residues, we can see that P-gphas the ability to combine various types of drug molecules (including drugsmacromolecules). Our analysis provides structural information of flexibility of Pgp andthe source of its poly-specific drug binding..In the second part, we construct outward-facing P-gp based on Msba structure andperform10ns molecular dynamics to compare with MD of inward-facing P-gp. Different from the inward-facing model, the outward-facing P-gp’s structural changes inthe dynamics and some residues changing show that the transmembrane parts of P-gpprotein are twisted, which is helpful for the discharge of drug molecules.