Computational and structural insights into the pre- and post-hydrolysis states of bovine multidrug resistance associated protein 1 (MRP1)

ATP-binding cassette C-family drug membrane transporters play an important role in local pharmacokinetics, i.e ., drug concentration in cellular compartments. From the structural point of view, only the bovine ortholog of the multidrug-resistance associated protein 1 ( b MRP1) has been resolved. We here used μs-scaled molecular dynamics simulations to investigate the structure and dynamics of b MRP1 in pre- and post-hydrolysis functional states. The present work aims to examine the slight but likely relevant structural differences between pre- and post-hydrolysis states of outward-facing conformations as well as the interactions between MRP1 and the surrounding lipid bilayer. Global conformational dynamics show unfavourable extracellular opening associated with nucleotide binding domain dimerization indicating that the post-hydrolysis state adopts a close-cleft conformation rather than an outward-open conformation. Our present simulations also highlight persistent interactions with annular cholesterol molecules and the expected active role of lipid bilayer in the allosteric communication between distant domains of MRP1 transporter.