Lactose permease of Escherichia coli (LacY) catalyzes symport of a
galactopyranoside and an H+ via an alternating access mechanism. The
transition from an inward- to an outward-facing conformation of LacY involves
sugar-release followed by deprotonation. Because the transition depends
intimately upon the dynamics of LacY in a bilayer environment, molecular
dynamics (MD) simulations may be the only means of following the accompanying
structural changes in atomic detail. Here, we describe MD simulations of wild-
type apo LacY in phosphatidylethanolamine (POPE) lipids that features two
protonation states of the critical Glu325. While the protonated system
displays configurational stability, deprotonation of Glu325 causes significant
structural rearrangements that bring into proximity side chains important for
H+ translocation and sugar binding and closes the internal cavity. Moreover,
protonated LacY in phosphatidylcholine (DMPC) lipids shows that the observed
dynamics are lipid-dependent. Together, the simulations describe early
dynamics of the inward-to-outward transition of LacY that agree well with
experimental data