Computational modeling reveals that altered tropomyosin positioning is sufficient to explain the hypercontractility seen with R92Q. (A) Using the computational model developed by Campbell et al. (2010) and the measured equilibrium constants for thin filament activation, the steady-state force per sarcomere was calculated. Changing K_B alone is sufficient to reproduce the shift toward submaximal calcium activation seen in the in vitro motility experiments (Fig. 2 A). (B) Using the same model, the equilibrium constants measured in vitro, and the calcium transients measured in hiPSC-CMs (Fig. 6 A), the twitch force (solid line) in response to a calcium transient (dashed line) was calculated. Consistent with our cellular measurements, the simulations demonstrate that despite having a reduced calcium transient, R92Q produces a larger force in a twitch due to changes in tropomyosin positioning.