Demonstrates that labda DNA force-extension curves are well modeled as WLCs, introducing WLCs in the context of force spectroscopy.
Unfolding and theory. Example on ligand-receptor binding.
First force spectroscopy on a multi-globular single protein. Reversible suggests unfolding of individual domains.
Geometry argument for pulling angle irrelevance.
Unfolding not due to pulling domains off the substrate surface.
First force spectroscopy on synthesized multi-globular I27. Comparisons of unfolding constants with chemical techniques.
Extend Kramers’ theory to determine energy landscape roughness.
Previous measurements on temperature dependent protein unfolding.
pages 115–116 and Figure 2.a
Discusses energy landscape curvature and rebinding effects. (Aha, this is what Noy wanted me to talk about).
Biophys J, 94 (2008), 7 2621–2630.
Energy landscape E E* = E(x) + ½kx² E** = E(x) - Fx + ½kx² F_b = x_b/k_B T k_off = k₀ exp([F_R - ½kx_b]/F_b)
Competetion between number of parallel unfolders and effective loading rate. The unfolding rate must be binned somehow, and the scaffold effect makes binning difficult. k(F,Delta F,kappa) = unfolding rate of proteins present within Delta F of an average tension F applied via a linker of stiffness kappa=dF/dx (kappa to deal with the Cantilever spring constant effect. I suggest we use the censored survival statistics common to medical studies, and hopefully see exponential decay for each force. We’ll probably have to lump similar loading rates (=kappa∙v) together, and the more gently loaded proteins will survive longer (having a lower mean force after the same length of time in the [F, F+Delta F] bin). The general trend will also be towards accelerated exponential decay, since the mean forces of all proteins will increase throughout the bin.
Protein Science, 11 (2002), 12 2759–2765. Monte Carlo simulation and experiment on I27 and mutants.
“Nonparametric estimation from incomplete observations,” Journal of the American Statistical Association, 53, 457-481 (1958).
“The Mean, Median, and Confidence Intervals of the Kaplan-Meier Survival Estimate—Computations and Applications,” The American Statistician, 63(1), 78–80 (2009). DOI 10.1198/tast.2009.0015
“Two-Sided Confidence Intervals for the Single Proportion: Comparison of Seven Methods,” Statistics in Medicine, 17, 857-872 (1998).
“Probable Inference, the Law of Succession, and Statistical Inference,” Journal of the American Statistical Association, 22, 209-212 (1927).
“The natural duration of cancer.” Reports on Public Health and Medical Subjects 33, 1–26. Her Majesty’s Stationery Office, London.
“Statistical Methods for Reliability Data”, John Wiley & Sons, Inc., New York, 1998. Greenwood’s formula for Kaplan-Meier error. Example calculations: http://www.weibull.com/LifeDataWeb/nonparametric_analysis.htm