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Single-molecule force spectroscopy has opened a new field of research inmolecular biophysics and biochemistry. Pulling experiments on individualproteins permit us to monitor conformational transitions with high temporalresolution and measure their free energy landscape. The force-extension curvesof single proteins often present large hysteresis, with unfolding forces thatare higher than refolding ones. Therefore, the high energy of the transitionstate (TS) in these molecules precludes kinetic rates measurements inequilibrium hopping experiments. In irreversible pulling experiments,force-dependent kinetic rates measurements show a systematic discrepancybetween the sum of the folding and unfolding TS distances derived by thekinetic Bell-Evans model and the full molecular extension predicted by elasticmodels. Here, we show that this discrepancy originates from the force-inducedmovement of TS. Specifically, we investigate the highly kinetically stableprotein barnase, using pulling experiments and the Bell-Evans model tocharacterize the position of its kinetic barrier. Experimental results showthat while the TS stays at a roughly constant distance relative to the nativestate, it shifts with force relative to the unfolded state. Interestingly, aconversion of the protein extension into amino acid units shows that the TSposition follows the Leffler-Hammond postulate: the higher the force, the lowerthe number of unzipped amino acids relative to the native state. The resultsare compared with the quasi-reversible unfolding-folding of a short DNAhairpin.

Force Dependence of Proteins' Transition State Position and the Bell-Evans Model