At a gross structural level two conclusions are evident. First, the overall structure of the catalytic domain, and the architecture of the MCR-1 active site, appear to be little affected by the presence of the transmembrane domain; as evidenced by comparison with our previous simulations of the periplasmic domain , and the consistency of overall RMSD values for simulations carried out under the eight different sets of conditions (Figure ). Second, while there is limited motion of the two domains relative to one another, as adjudged by measurements between the respective centers of mass (Figure ), we do not observe the more profound rearrangements described by Anandan et al in their simulations of N. meningitidis EptA 14 , in which the catalytic domain retains only minimal contact with the transmembrane domain and instead makes extensive interactions with the polar headgroups of the membrane lipids. While under the conditions of our simulations it is possible for the two domains to move relative to one another, in none of the eight combinations of donor substrate, alternative zinc stoichiometry and Thr285 modification did we observe the c. 15 Å increase in separation of centers of mass that indicated the profound conformational change described for EptA. This is true in simulations run at both 300 and 310 K, replicating both types of conditions under which this conformational change was observed.