Tropomyosin movement on F-actin during muscle activation explained by energy landscapes

•An energy landscape was calculated for tropomyosin on the surface of F-actin.•The energy minimum locates tropomyosin near its myosin-blocking position on F-actin.•Tropomyosin’s myosin-induced open-position is near to the landscape’s energy maximum.•Myosin-binding drives tropomyosin uphill over F-actin to activate thin filaments.•Mutations distort the energy landscape in ways that explain phenotypic traits.

Muscle contraction is regulated by tropomyosin movement across the thin filament surface, which exposes or blocks myosin-binding sites on actin. Recent atomic structures of F-actin–tropomyosin have yielded the positions of tropomyosin on myosin-free and myosin-decorated actin. Here, the repositioning of α-tropomyosin between these locations on F-actin was systematically examined by optimizing the energy of the complex for a wide range of tropomyosin positions on F-actin. The resulting energy landscape provides a full-map of the F-actin surface preferred by tropomyosin, revealing a broad energy basin associated with the tropomyosin position that blocks myosin-binding. This is consistent with previously proposed low-energy oscillations of semi-rigid tropomyosin, necessary for shifting of tropomyosin following troponin-binding. In contrast, the landscape shows much less favorable energies when tropomyosin locates near its myosin-induced “open-state” position. This indicates that spontaneous movement of tropomyosin away from its energetic “ground-state” to the open-state is unlikely in absence of myosin. Instead, myosin-binding must drive tropomyosin toward the open-state to activate the thin filament. Additional energy landscapes were computed for disease-causing actin mutants that distort the topology of the actin–tropomyosin energy landscape, explaining their phenotypes. Thus, the computation of such energy landscapes offers a sensitive way to estimate the impact of mutations.

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