Nucleotide asymmetry and flexible linker dynamics modulate drug efflux cycle of P-glycoprotein, A computational study.

ABSTRACT: Despite advancements in oncology, multidrug resistance (MDR) mediated by P-glycoprotein (P-gp/ABCB1) remains a major barrier to chemotherapy. P-gp is an ATP-binding cassette transporter that undergoes nucleotide-driven structural rearrangements to efflux chemotherapeutics, but the mechanistic details of the substrate transport remain poorly resolved. Here, we performed high-throughput multi-replica molecular dynamics to simulate P-gp in a lipid bilayer (totaling ∼110 µs) to dissect nucleotide-dependent conformational changes across the transport cycle. Our adaptive sampling strategy reveals asymmetric nucleotide coordination at nucleotide-binding sites (NBS), which correlates with transmembrane domain (TMD) restructuring for substrate efflux. The experimentally unresolved flexible linker t

SUBMITTER: Han SB 

PROVIDER: S-EPMC12636386 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature