High-Speed Force Spectroscopy Unfolds Titin at the Velocity of Molecular Dynamics Simulations

Science  08 Nov 2013:
Vol. 342, Issue 6159, pp. 741-743
DOI: 10.1126/science.1239764

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Bridging the Titin Gap

The muscle protein titin is a molecular spring that has been extensively studied by single-molecule unfolding experiments and by molecular simulation. However, experimental and simulated unfolding could not be compared directly because they differ by orders of magnitude in pulling velocity. Rico et al. (p 741) developed high-speed force spectroscopy to pull titin molecules at speeds that reach the lower limits of molecular dynamics simulations. Bridging the gap between simulation and experiment clarified the mechanism of conformational changes in titin.


The mechanical unfolding of the muscle protein titin by atomic force microscopy was a landmark in our understanding of single-biomolecule mechanics. Molecular dynamics simulations offered atomic-level descriptions of the forced unfolding. However, experiment and simulation could not be directly compared because they differed in pulling velocity by orders of magnitude. We have developed high-speed force spectroscopy to unfold titin at velocities reached by simulation (~4 millimeters per second). We found that a small β-strand pair of an immunoglobulin domain dynamically unfolds and refolds, buffering pulling forces up to ~100 piconewtons. The distance to the unfolding transition barrier is larger than previously estimated but is in better agreement with atomistic predictions. The ability to directly compare experiment and simulation is likely to be important in studies of biomechanical processes.

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