Detection of Rare Misfolding Events

During refolding experiments "skip" events have been observed. Analysis of their contour lengths suggests that these are due to the formation of a "superfold" upon refolding, which includes two consecutive domains and the linker region between them (Fig. 8.5e). Ms misfolded "superdomain" unfolds at forces similar to those of a single domain and refolds back to two normal domains. SMFS of the titin poly-127 and the fnlll domains of tenascin have demonstrated the power of these single-molecule studies in detecting rare events, which occur in a small number of molecules within the population (2-4%). In this way, the efficiency (i.e., fidelity) of refolding after mechanical unfolding can be estimated (Oberhauser et al. 1999). Such unusual unfolding events could not be observed using ensemble techniques and they open the door to investigate the means of reversing undesirable misfolding processes that occur in the cell in a number of pathological conditions.

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