In previous work we applied structural, microbiological and computational methods to investigate the mechanism of the MCR-1 phosphoethanolamine transferase, focusing on the isolated periplasmic catalytic domain as a tractable model system. Here we extend these studies to address the behavior of the intact (full-length) enzyme, including both the catalytic and N-terminal transmembrane (TMD) domains, in a representative E. coli inner membrane system; focusing on the interactions between the two domains and of the full-length protein with the zinc cofactor and palmitoyloleoyl phosphoethanolamine (POPE) donor substrate. In the absence of an experimental structure of full-length MCR-1, these investigations utilized an homology model (Figure ) constructed based on our experimental structure of the MCR-1 catalytic domain (PDB 5LRN ) and on the crystal structure of the homologous Neisseria meningitidis EptA enzyme (PDB 5FGN ). The model comprises MCR-1 residues 11 -541; with the first ten residues, that form an unstructured N-terminal tail, being excluded due to the absence of any predicted secondary structure, structural or catalytic function; as well as their situation far from the active site. The model was then tested in extended (triplicate 500 ns) molecular dynamics (MD) simulations in a rectangular model membrane system comprising a mixture of POPE and palmitoyloleoyl phosphatidylglycerol (POPG) in an 80:20 ratio. Eight sets of simulations tested MCR-1 in the mono-and dizinc forms, each in the presence and absence of a molecule of POPE docked into the active site cavity and with and without covalent attachment of phosphoethanolamine (PEtN) to the catalytic threonine residue Thr285. Simulations involving the PEtN-bound forms then represent possible states of the intermediate, expected to be formed after transfer of PEtN from a POPE donor to MCR-1, prior to reaction with the lipid A PEtN acceptor.