ATP-binding cassette (ABC) transporters couple ATP binding and hydrolysis to large-scale conformational changes that ultimately lead to the translocation of substrates across biological membranes. Despite impressive progress in experimental structural biology of transporters, also including several structures of substrate-bound exporters, the details of the – inherently dynamic – substrate transport pathways and their coupling to the conformational motions of the transporter remain to be resolved at the atomic level. Here, results from all-atom molecular dynamics (MD) simulations of the heterodimeric ABC exporter TM287/288 from the thermophilic bacterium <i>T. maritima</i> are presented. The unguided multi-microsecond MD simulations reveal the dynamic translocation pathways of the drugs daunorubicin and verapamil through the transporter. The drugs follow the spontaneous large-scale alternating access transition of the transporter from the initial inward-facing (IF) conformation via an occluded intermediate to an outward-facing (OF) conformation. Differential hydration of the substrate binding cavity in the IF and OF conformations leads to an affinity difference between the two conformations that triggers the dissociation of the drugs from the OF conformation and favors the partitioning into the lipid bilayer, thereby preventing substrate reuptake.

Spontaneous substrate translocation in an ABC exporter

ACS Fall 2021

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