TY - JOUR
T1 - Modeling substrate entry into the P-glycoprotein efflux pump at the blood-brain barrier
AU - Jorgensen, Christian
AU - Ulmschneider, Martin B.
AU - Searson, Peter C.
N1 - Funding Information:
The authors gratefully acknowledge support from the National Institutes of Health (R01NS106008, R61/33 HL154252, and R21NS131831) and DTRA (HDTRA1-15-1-0046). This research project was conducted using computational resources at the Maryland Advanced Research Computing Center (MARCC). The authors thank insightful discussion with Erin Gallagher and Raleigh Linville. C.J. acknowledges support from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 101023783.
Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/12/14
Y1 - 2023/12/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85181028006&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.3c01069
DO - 10.1021/acs.jmedchem.3c01069
M3 - Article
C2 - 38097510
AN - SCOPUS:85181028006
SN - 0022-2623
VL - 66
SP - 16615
EP - 16627
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 24
ER -