title: Probing the flexibility of tropomyosin and its binding to filamentous actin using molecular dynamics simulations.
abstract: Tropomyosin (Tm) is a coiled-coil protein that binds to filamentous actin (F-actin) and regulates its interactions with actin-binding proteins like myosin by moving between three positions on F-actin (the blocked, closed, and open positions). To elucidate the molecular details of Tm flexibility in relation to its binding to F-actin, we conducted extensive molecular dynamics simulations for both Tm alone and Tm-F-actin complex in the presence of explicit solvent (total simulation time >400 ns). Based on the simulations, we systematically analyzed the local flexibility of the Tm coiled coil using multiple parameters. We found a good correlation between the regions with high local flexibility and a number of destabilizing regions in Tm, including six clusters of core alanines. Despite the stabilization by F-actin binding, the distribution of local flexibility in Tm is largely unchanged in the absence and presence of F-actin. Our simulations showed variable fluctuations of individual Tm periods from the closed position toward the open position. In addition, we performed Tm-F-actin binding calculations based on the simulation trajectories, which support the importance of Tm flexibility to Tm-F-actin binding. We identified key residues of Tm involved in its dynamic interactions with F-actin, many of which have been found in recent mutational studies to be functionally important, and the rest of which will make promising targets for future mutational experiments.
authors.affiliation: Department of Physics, University at Buffalo, Buffalo, New York. Electronic address: wjzheng@buffalo.edu.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zheng
authors.forename: Bipasha
authors.initials: B
authors.lastname: Barua
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hitchcock-DeGregori
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D018583:Pliability; D011485:Protein Binding; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000378:metabolism; D014335:Tropomyosin / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000199:Actins; D021122:Protein Subunits; D014335:Tropomyosin