TY - JOUR
T1 - Force-clamp analysis techniques give highest rank to stretched exponential unfolding kinetics in ubiquitin
AU - Lannon, Herbert
AU - Vanden-Eijnden, Eric
AU - Brujic, J.
N1 - Funding Information:
We thank Jin Montclare for the expression of the ubiquitin polyprotein and Maxime Clusel for useful discussions. J.B. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. This work was supported partially by the MRSEC Program of the National Science Foundation under award No. DMR-0820341 and the National Science Foundation Career Award 0955621.
PY - 2012/11/21
Y1 - 2012/11/21
N2 - Force-clamp spectroscopy reveals the unfolding and disulfide bond rupture times of single protein molecules as a function of the stretching force, point mutations, and solvent conditions. The statistics of these times reveal whether the protein domains are independent of one another, the mechanical hierarchy in the polyprotein chain, and the functional form of the probability distribution from which they originate. It is therefore important to use robust statistical tests to decipher the correct theoretical model underlying the process. Here, we develop multiple techniques to compare the well-established experimental data set on ubiquitin with existing theoretical models as a case study. We show that robustness against filtering, agreement with a maximum likelihood function that takes into account experimental artifacts, the Kuiper statistic test, and alignment with synthetic data all identify the Weibull or stretched exponential distribution as the best fitting model. Our results are inconsistent with recently proposed models of Gaussian disorder in the energy landscape or noise in the applied force as explanations for the observed nonexponential kinetics. Because the physical model in the fit affects the characteristic unfolding time, these results have important implications on our understanding of the biological function of proteins.
AB - Force-clamp spectroscopy reveals the unfolding and disulfide bond rupture times of single protein molecules as a function of the stretching force, point mutations, and solvent conditions. The statistics of these times reveal whether the protein domains are independent of one another, the mechanical hierarchy in the polyprotein chain, and the functional form of the probability distribution from which they originate. It is therefore important to use robust statistical tests to decipher the correct theoretical model underlying the process. Here, we develop multiple techniques to compare the well-established experimental data set on ubiquitin with existing theoretical models as a case study. We show that robustness against filtering, agreement with a maximum likelihood function that takes into account experimental artifacts, the Kuiper statistic test, and alignment with synthetic data all identify the Weibull or stretched exponential distribution as the best fitting model. Our results are inconsistent with recently proposed models of Gaussian disorder in the energy landscape or noise in the applied force as explanations for the observed nonexponential kinetics. Because the physical model in the fit affects the characteristic unfolding time, these results have important implications on our understanding of the biological function of proteins.
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U2 - 10.1016/j.bpj.2012.10.022
DO - 10.1016/j.bpj.2012.10.022
M3 - Article
C2 - 23200055
AN - SCOPUS:84869425184
VL - 103
SP - 2215
EP - 2222
JO - Biophysical Journal
JF - Biophysical Journal
SN - 0006-3495
IS - 10
ER -