The Mechanical Stability of the Titin Z1Z2/Telethonin Complex revealed by Steered Molecular Dynamics Simulations

The giant muscle protein titin, which provides a passive restoring force upon extension, is essential for maintaining the integrity of the muscular sarcomere. In order for titin to reversibly stretch and contract, the ends of this protein must be constrained, or anchored, at its terminal domains at the sarcomeric Z-disc and M-line. Here we investigate the role that telethonin, a protein which joins the ends of two titin molecules together at the Z-disc, plays in anchoring titin to one end of the sarcomere. Using molecular dynamics (MD) simulations, we have explored the mechanical properties of the recently solved titin Z1Z2-telethonin complex, namely, its ability to bear strong forces such as those titin may encounter during passive muscle stretch. Our results show that not only does this complex resist high levels of mechanical force, suggesting that telethonin is the N-terminal titin anchor, but also that telethonin acts to distribute these forces between its two joined titin Z2 domains to protect the proximal Z1 domain from unfolding under stress. Our study sheds light on a key architectural function of biological cells, the formation of strong mechanical links between separate proteins through molecular glues that naturally need to be carefully controlled to avoid pathological aggregation.