Integrative Structural Modelling of the Cardiac Thin Filament: Energetics at the Interface and Conservation Patterns Reveal a Spotlight on Period 2 of Tropomyosin

Cardiomyopathies are a major health problem, with inherited cardiomyopathies, many of which are caused by mutations in genes encoding sarcomeric proteins, constituting an ever-increasing fraction of cases. To begin to study the mechanisms by which these mutations cause disease, we have employed an integrative modelling approach to study the interactions between tropomyosin and actin. Starting from the existing blocked state model, we identified a specific zone on the actin surface which is highly favourable to support tropomyosin sliding from the blocked/closed states to the open state. We then analysed the predicted actin-tropomyosin interface regions for the three states. Each quasi-repeat of tropomyosin was studied for its interaction strength and evolutionary conservation to focus on smaller surface zones. Finally, we show that the distribution of the known cardiomyopathy mutations of α-tropomyosin is consistent with our model. This analysis provides structural insights into the possible mode of interactions between tropomyosin and actin in the open state for the first time.Video Abstract