title: Molecular basis of the mechanical hierarchy in myomesin dimers for sarcomere integrity.
abstract: Myomesin is one of the most important structural molecules constructing the M-band in the force-generating unit of striated muscle, and a critical structural maintainer of the sarcomere. Using molecular dynamics simulations, we here dissect the mechanical properties of the structurally known building blocks of myomesin, namely α-helices, immunoglobulin (Ig) domains, and the dimer interface at myomesin's 13th Ig domain, covering the mechanically important C-terminal part of the molecule. We find the interdomain α-helices to be stabilized by the hydrophobic interface formed between the N-terminal half of these helices and adjacent Ig domains, and, interestingly, to show a rapid unfolding and refolding equilibrium especially under low axial forces up to ∼ 15 pN. These results support and yield atomic details for the notion of recent atomic-force microscopy experiments, namely, that the unique helices inserted between Ig domains in myomesin function as elastomers and force buffers. Our results also explain how the C-terminal dimer of two myomesin molecules is mechanically outperforming the helices and Ig domains in myomesin and elsewhere, explaining former experimental findings. This study provides a fresh view onto how myomesin integrates elastic helices, rigid immunoglobulin domains, and an extraordinarily resistant dimer into a molecular structure, to feature a mechanical hierarchy that represents a firm and yet extensible molecular anchor to guard the stability of the sarcomere.
authors.affiliation: Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
authors.forename: Senbo
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Heidelberg Institute for Theoretical Studies, Heidelberg, Germany; Chinese Academy of Sciences-Max-Planck-Society Partner Institute and Key Laboratory for Computational Biology, Shanghai, China; Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany. Electronic address: frauke.graeter@h-its.org.
authors.forename: Frauke
authors.initials: F
authors.lastname: Gräter
mesh_terms: D001696:Biomechanical Phenomena; D064211:Connectin / Q000235:genetics / Q000378:metabolism*; D004548:Elasticity; D057927:Hydrophobic and Hydrophilic Interactions; D007136:Immunoglobulins / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D058849:Protein Refolding; D017433:Protein Structure, Secondary; D058767:Protein Unfolding; D012518:Sarcomeres / Q000378:metabolism*
chemical_list: D064211:Connectin; D007136:Immunoglobulins