Stochastic thermodynamics of hERG gating models

The central role Kv11.1(hERG), a potassium ion channel, plays in mediating I_kr and its association with cardiac irregularity makes understanding and effectively modeling Kv11.1 necessary for disease and drug modeling. Several models of Kv11.1 have been proposed and investigated to better understand its gating kinetics and subsequent electrophysiological function both in vivo and in controlled cell lines. Despite decades of productive research, limited access (in quality, quantity, and dimensionality) to ground truth data makes it difficult to meaningfully distiguish between similarly performing models. We employ recent tools from nonequilibrium thermodynamics to examine and contrast a selection of Markov models of Kv11.1 surveyed by Bett et al. (Biophys. J. 101:631–642, 2011) in terms of their energetic and entropic responses to a variety of driving voltage protocols. In doing so, we (i) calculate in detail previously sampled maximum tail current, (ii) reveal novel thermodynamic consequences predicted by these model class, structure, and parameterization choices, and (iii) propose leveraging these tools as additional differentiators for model selection.