The steps involved in co-translational TM interfacial headgroup partitioning, bilayer insertion and folding either without (A) or with (B) the translocon. Folding begins while later TMs are being translated and inserted in the bilayer. Some of these stages, and free energies associated with each stage, are the same as those measured using in vitro methods (as illustrated in Figure 2). We use the models in this figure to highlight the similarities and differences in pathways between translocon-assisted and spontaneous TM insertion and membrane protein folding, and to show that interactions between the nascent chain and the lipid bilayer are involved in all stages.