Multi-antimicrobial extrusion (MATE) transporter membrane proteins provide drug and toxin resistivity by expelling compounds from cells. MATE proteins can be pictured as V-shaped. To regulate its functioning, the protein structure can switch between outward-facing (OF) and inward-facing (IF). Pyrococcus furiosus MATE (PfMATE) is the only member of the multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) superfamily that has available both the IF and OF crystal structures. With the availability of the both the IF and OF structures, we are able to perform computational investigations to determine how protonation of specific amino acids causes a cascade of changes in the protein conformation that allow PfMATE to change its state from OF to IF in order to regulate its antiporter function. Using a variety of computational techniques, we investigated four different systems of IF and OF PfMATE along with the native archaeal lipid bilayer, without or with protonation at the experimentally determined locations within the protein. We performed molecular dynamics (MD) simulations to investigate the flexibility of the four different PfMATE structures, and also performed targeted molecular dynamics (TMD) simulations during which we observe occluded conformations. Our analysis of hydrogen bond changes, potential of mean force, dynamic network analysis, and transfer entropy analysis provides information on how protonation can induce cascading structural changes responsible for the transition between the IF and OF configurations.