Numerical analysis of interaction energies computed via FMC and GIA using the ZHA model. (A) The ZHA model of activation of the Shaker KV channel. A mutant cycle is envisioned in which the WT channel and the mutants gate via the ZHA scheme. The two single mutants (hashed box and gray box) differ from the WT reference channel (open box) only in the value of the last concerted transition (by factors of p1 and p2). The effects of the two single mutants are additive such that for the double mutant (gray hashed box) the equilibrium constant of the last transition is p1p2L, whereas the other equilibrium constants are same as the WT channel. (B and C) Several such cycles were generated using different values of p1 and p2, and for each cycle, ΔΔGFMC (B) and ΔΔGGIA (C) were calculated from simulated PO-V and Q-V curves, respectively, and plotted against p1 and p2.
