Insights into conformational regulation of PfMATE transporter from Pyrococcus furiosus induced by alternating protonation state of Asp41 residue: A molecular dynamics simulation study

Background Multidrug and toxic compound extrusion (MATE) family transporters induce multiple-drug resistance (MDR) of bacterial pathogens and cancer cells, thus causing critical reductions in the therapeutic efficacies of antibiotics and anti-cancer drugs. Unfortunately, to date, the details and intrinsic reason about conformational regulation mechanism of MATE transporters remain elusive. Method In this work, molecular dynamics (MD) simulations were conducted to explore the conformational regulation mechanism of PfMATE transporter from Pyrococcus furiosus based on different protonation state of Asp41. Two (MD) simulation systems were investigated: A system with protonation of Asp41 and a system without protonation of Asp41, which were named by D184(H)D41(H) system and D184(H) system, respectively. Results and conclusions Firstly, MD simulation results indicate that conformational changes mainly happen in extracellular regions of PfMATE protein. Further analysis reveals that PfMATE protein experiences different motion mode and forms different conformation based on different protonation state of Asp41. In the D184(H)D41(H) system, PfMATE experiences an opening motion and forms a more outward-open conformation. As for the D184(H) system, the protein has an anticlockwise rotational motion with the channel axis of protein and the more outward-open conformation does not appear. It can be inferred that protonation of Asp41 is essential for conformational regulation of PfMATE during transporting substrates. General significance These findings provide intrinsic information for understanding the conformational regulation mechanism of PfMATE and will be very meaningful to explore the MDR mechanism of PfMATE further.