Modeling substrate entry into the P-glycoprotein efflux pump at the blood-brain barrier

Christian Jorgensen, Martin B. Ulmschneider, Peter C. Searson*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    Abstract

    We report molecular dynamics simulations of rhodamine entry into the central binding cavity of P-gp in the inward open conformation. Rhodamine can enter the inner volume via passive transport across the luminal membrane or lateral diffusion in the lipid bilayer. Entry into the inner volume is determined by the aperture angle at the apex of the protein, with a critical angle of 27° for rhodamine. The central binding cavity has an aqueous phase with a few lipids, which significantly reduces substrate diffusion. Within the central binding cavity, we identified regions with relatively weak binding, suggesting that the combination of reduced mobility and weak substrate binding confines rhodamine to enable the completion of the efflux cycle. Tariquidar, a P-gp inhibitor, aggregates at the lower arms of the P-gp, suggesting that inhibition involves steric hindrance of entry into the inner volume and/or steric hindrance of access of ATP to the nucleotide-binding domains.

    Original languageEnglish
    Pages (from-to)16615-16627
    Number of pages13
    JournalJournal of Medicinal Chemistry
    Volume66
    Issue number24
    DOIs
    Publication statusPublished - 14 Dec 2023

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