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One of the most intriguing results of single molecule experiments on proteinsand nucleic acids is the discovery of functional heterogeneity: the observationthat complex cellular machines exhibit multiple, biologically activeconformations. The structural differences between these conformations may besubtle, but each distinct state can be remarkably long-lived, with randominterconversions between states occurring only at macroscopic timescales,fractions of a second or longer. Though we now have proof of functionalheterogeneity in a handful of systems---enzymes, motors, adhesioncomplexes---identifying and measuring it remains a formidable challenge. Herewe show that evidence of this phenomenon is more widespread than previouslyknown, encoded in data collected from some of the most well-established singlemolecule techniques: AFM or optical tweezer pulling experiments. We present atheoretical procedure for analyzing distributions of rupture/unfolding forcesrecorded at different pulling speeds. This results in a single parameter,quantifying the degree of heterogeneity, and also leads to bounds on theequilibration and conformational interconversion timescales. Surveying tenpublished datasets, we find heterogeneity in five of them, all withinterconversion rates slower than 10 s$^{-1}$. Moreover, we identify twosystems where additional data at realizable pulling velocities is likely tofind a theoretically predicted, but so far unobserved cross-over regime betweenheterogeneous and non-heterogeneous behavior. The significance of this regimeis that it will allow far more precise estimates of the slow conformationalswitching times, one of the least understood aspects of functionalheterogeneity.

Directly measuring single molecule heterogeneity using force spectroscopy