On the energetics of translocon-assisted insertion of charged transmembrane helices into membranes

The understanding of the mechanism of insertion of transmembrane (TM) helixes through the translocon presents a major open challenge. Although the experimental information about the partition of the inserted helices between the membrane and the solution contains crucial information about this process, it is not clear how to extract this information. In particular, it is not clear how to rationalize the small apparent insertion energy, ΔGapp, of an ionized residue in the center of a TM helix. Here we explore the nature of the insertion energies, asking what should be the value of these parameters if their measurements represent equilibrium conditions. This is done using a coarse-grained model with advanced electrostatic treatment. Estimating the energetics of ionized arginine of a TM helix in the presence of neighboring helixes or the translocon provides a rationale for the observed ΔGapp of ionized residues. It is concluded that the apparent insertion free energy of TM with charged residues reflects probably more than just the free energy of moving the isolate single helix from water into the membrane. The present approach should be effective not only in exploring the mechanism of the operation of the translocon but also for studies of other membrane proteins.