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The nature of the biological free energy scale (ΔGapp), obtained from translocon mediated insertion studies, has been a major puzzle and the subject of major controversies. Part of the problem has been the complexity of the insertion process that discouraged workers from considering the feasible kinetics schemes and left the possible impression that ΔGapp presents some simple partition. Here we extend and clarify our recent analysis of the insertion problem using well-defined kinetics schemes and a free energy profile. We point out that although the rate constants of some steps are far from being obvious, it is essential to consider explicitly such schemes in order to advance in analyzing the meaning of ΔGapp. It is then shown that under some equilibrium conditions the kinetics scheme leads to a simple formula that allows one to relate ΔGapp to the actual free energy of partitioning between the water, the membrane, and the translocon. Other options are also considered (including limits with irreversible transitions that can be described by linear free energy relationships (LFERs)). It is concluded that it is unlikely that a kinetics plus thermodynamic based analysis can lead to a result that identifies ΔGapp with the partition between the membrane and the translocon. Thus, we argue that unless such analysis is presented, it is unjustified to assume that ΔGapp corresponds to the membrane translocon equilibrium or to some other arbitrary definition. Furthermore, we point out that the presumption that it is sufficient to just calculate the PMF for going from the translocon (TR) to the membrane and then to assume irreversible diffusive motion to water and for further entrance to the membrane is not a valid analysis. Overall, we point out that it is important to try to relate ΔGapp to a well-defined kinetics scheme (regardless of the complication of the system) in order to determine whether the energies of inserting positively charged residues to the membrane are related to the corresponding ΔGapp. It is also suggested that deviations from our simple formula for equilibrium conditions can help in identifying and analyzing kinetics barriers.

On the Nature of the Apparent Free Energy of Inserting Amino Acids into Membrane through the Translocon