title: Molecular investigations into the mechanics of a muscle anchoring complex.
abstract: The titin-telethonin complex, essential for anchoring filaments in the Z-disk of the sarcomere, is composed of immunoglobulin domains. Surprisingly, atomic force microscopy experiments showed that it resists forces much higher than the typical immunoglobulin domain and that the force distribution is unusually broad. To investigate the origin of this behavior, we developed a multiscale simulation approach, combining minimalist and atomistic models (SOP-AT). By following the mechanical response of the complex on experimental timescales, we found that the mechanical stability of titin-telethonin is modulated primarily by the strength of contacts between telethonin and the two titin chains, and secondarily by the timescales of conformational excursions inside telethonin and the pulled titin domains. Importantly, the conformational transitions executed by telethonin in simulations support its proposed role in mechanosensing. Our SOP-AT computational approach thus provides a powerful tool for the exploration of the link between conformational diversity and the broadness of the mechanical response, which can be applied to other multidomain complexes.
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Bodmer
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Theisen
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, Ohio. Electronic address: dimari@ucmail.uc.edu.
authors.forename: Ruxandra I
authors.initials: RI
authors.lastname: Dima
mesh_terms: D000595:Amino Acid Sequence; D001696:Biomechanical Phenomena; D064211:Connectin / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009038:Motion; D009124:Muscle Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C507454:Tcap protein, rat