A range of voltage-clamp protocol designs for rapid capture of hERG kinetics

Figures

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  Figure 1.. The model structures used for experimental design. ( a): the four-state Beattie et al. (2018) model. ( b): the five-state Wang et al. (1997) model. The arrows adjacent to each model structure indicate the direction in which rates increase as the voltage increases. Reproduced from Shuttleworth et al. (2024) under a CC-BY licence.

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  Figure 2.. The manually-designed staircase protocol used in Lei, Clerx, Beattie, et al. (2019a; Lei et al., 2019b) and its simulation, with state occupancy shown for the Beattie et al. (2018) model of Figure 1a. Reproduced from ( Lei et al., 2019b) under a CC-BY licence.

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  Figure 3.. Manual designs. Top: the staircase-in-staircase (sis) protocol. Bottom: the ‘inverted’ staircase-in-staircase (sisi) protocol. Underneath each protocol are simulated currents from the two models ( hh_ikr_rt is the Beattie et al. (2018) model of I Kr and wang_ikr_rt is the Wang et al. (1997) model of I Kr, both parameterised to room temperature data).

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  Figure 4.. More manual designs. Top: the manual phase space protocol (manualppx). Middle: the square wave protocol of Beattie et al. (2018) (squarewave). Bottom: the lumped action potential protocol (longap). Beneath each protocol we show simulated currents from both the Beattie and Wang models.

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  Figure 5.. The 3-step local sensitivity designs. Top: protocol based on the Hodgkin-Huxley model (hh3step). Bottom: based on the Wang model (wang3step). With simulated currents from both models shown below the protocols.

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  Figure 6.. The 3-step Sobol sensitivity protocols. Top: based on the Hodgkin-Huxley model (hhsobol3step). Bottom: based on the Wang model (wangsobol3step). With simulated currents from both models shown below the protocols.

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  Figure 7.. The brute-force sampling protocols. Top: based on the Hodgkin-Huxley model (hhbrute3gstep). Bottom: based on the Wang model (wangbrute3gstep). Simulated currents from both models are shown beneath each protocol.

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  Figure 8.. Protocols that maximise the difference between currents from the Beattie and Wang models. Top: based on randomised voltage and optimising time steps (rvotmaxdiff). Bottom: based on randomised time steps and optimised voltages (rtovmaxdiff). Simulated currents from both models are shown beneath each protocol.

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  Figure 9.. Phase-voltage space filling designs. Top: first phase-voltage space protocol (spacefill26). Middle: second phase-voltage space protocol (spacefill10). Bottom: third phase-voltage space protocol (spacefill19), with simulated currents from both models.

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  Figure 10.. The square wave protocol for maximising two models’ difference (maxdiff) and simulated currents from both models.