Molecular Dynamics Investigations of Inward-facing and Outward-facing Isomerization of PfMATE

The ability of the multidrug and toxic compound extrusion (MATE) transporters to expel chemical compounds out of the cell can result in multidrug resistance. Recently, both the inward-facing and outward-facing molecular structures have been determined for PfMATE, the MATE transporter of the archaeon Pyrococcus furiosus. This has allowed a deeper understanding of the mechanisms by which PfMATE is able to perform conformational transitions between inward- and outward-facing structures. To investigate this process, we performed molecular dynamics simulations of different systems of inward- and outward-facing PfMATE in the native archaeal lipid bilayer. The targeted molecular dynamics (TMD) simulations of the conformational transition between inward- and outward-facing structures of PfMATE have allowed us to quantify structure conversions by calculating the free-energy profiles using potential of mean force (PMF) calculations. The results show that the residues Asp41/Asp184 in either the deprotonated state or Na⁺-bound state favor the outward-facing conformation, whereas the protonated Asp184, Glu163, and Glu331 favor the inward-facing conformation.