title: Tropomyosin movement on F-actin during muscle activation explained by energy landscapes.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA; Computational Biochemistry Group, Interdisciplinary Center for Scientific Computing (IWR), University of Heidelberg, Im Neuenheimer Feld 368, Heidelberg D69120, Germany.
authors.forename: Marek
authors.initials: M
authors.lastname: Orzechowski
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Moore
authors.affiliation: Computational Biochemistry Group, Interdisciplinary Center for Scientific Computing (IWR), University of Heidelberg, Im Neuenheimer Feld 368, Heidelberg D69120, Germany. Electronic address: stefan.fischer@iwr.uni-heidelberg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA. Electronic address: wlehman@bu.edu.
authors.forename: William
authors.initials: W
authors.lastname: Lehman
mesh_terms: D000199:Actins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009038:Motion; D009132:Muscles / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D013816:Thermodynamics; D014335:Tropomyosin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000199:Actins; D014335:Tropomyosin
keywords: Actin; Coiled-coil; Energy landscape; Muscle regulation; Myosin; Thin filaments