Despite the increased attention to polymyxin antibiotic resistance that followed the discovery of MCR-1, there remains limited information describing interactions of the complete, full-length, protein, comprising both periplasmic catalytic and inner membrane transmembrane domains, with either its zinc cofactor(s) or its lipidated donor or acceptor substrates. Here we address this knowledge gap by applying extended molecular dynamics (MD) simulations to an homology model of full-length MCR-1 in a membrane environment. In previous MD simulations of the isolated periplasmic catalytic domain , based on crystal structures, we established that the overall structure is little affected by phosphorylation of the Thr285 acceptor (which can occur during expression/purification of the recombinant protein and has consequently been observed in experimental structures ), or by zinc stoichiometry, but metal binding to the Zn2 site is unstable. Based on these observations, and on density functional theory (DFT) and ab initio calculations on cluster of the MCR-1 active site , we proposed that MCR-1 acts by a "ping-pong" mechanism whereby phosphoethanolamine (PEtN) transfers from a lipidated, phosphatidylethanolamine donor to form a phosphointermediate at Thr285 in a reaction that requires a mono-zinc form of the enzyme. Subsequent PEtN transfer to the lipid A acceptor is then promoted by the di-zinc form of the enzyme, indicating that a second zinc equivalent is recruited to the MCR active site in either the phosphointermediate form or on lipid A binding. Alongside these findings, MD simulations by others, based on the crystal structure of the fulllength form of the N. meningitidis EptA PEtN transferase, identified this enzyme as able to access an "open" form in which the periplasmic domain repositions relative to the transmembrane domain and "rolls" over the surface of the membrane . We now investigate the dynamic behavior of full-length MCR-1 in extended MD simulations in a model membrane, simulating both mono-and di-zinc forms of the enzyme containing unmodified and phosphoethanolamine-linked forms of Thr285, in the presence and absence of the POPE donor substrate.