Recent efforts to broaden understanding of the molecular mechanisms of membrane receptors in signal transduction make use of rate-equilibrium free-energy relationships (REFERs), previously applied to chemical reactions, enzyme kinetics, and protein folding. For oligomeric membrane receptors, we distinguish between a), the Leffler parameter alpha(L), to characterize the global transition state for the interconversion between conformations; and b), the Fersht parameter, varphi(F), to assign the degree of progression of individual residue positions at the transition state. For both alpha(L) and varphi(F), insights are achieved by using harmonic energy profiles to reflect the dynamic nature of proteins, as illustrated with single-channel results reported for normal and mutant nicotinic receptors. We also describe new applications of alpha(L) based on published results. For large-conductance calcium-activated potassium channels, data are satisfactorily fit with an alpha(L) value of 0.65, in accord with REFERs. In contrast, results reported for the flip conformational state of glycine and nicotinic receptors are in disaccord with REFERs, since they yield alpha(L) values outside the usual limits of 0-1. Concerning published varphi(F) values underlying the conformational wave hypothesis for nicotinic receptors, we note that interpretations may be complicated by variations in the width of harmonic energy profiles.
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