Testing Kinetic Identities Involving Transition-Path Properties Using Single-Molecule Folding Trajectories

2018 ◽  
Vol 122 (49) ◽  
pp. 11095-11099 ◽  
Author(s):  
Krishna Neupane ◽  
Noel Q. Hoffer ◽  
Michael T. Woodside
Keyword(s):  
Single Molecule ◽  
Transition Path ◽  
Path Properties

scholarly journals Measurement of Average Transition-Path Time for Protein Folding in Single Molecule FRET Experiments

2012 ◽  
Vol 102 (3) ◽  
pp. 217a-218a
Author(s):  
Hoi Sung Chung ◽  
Irina V. Gopich ◽  
Kevin McHale ◽  
John M. Louis ◽  
William A. Eaton
Keyword(s):  
Protein Folding ◽  
Single Molecule ◽  
Transition Path ◽  
Single Molecule Fret ◽  
Average Transition

scholarly journals Broad distributions of transition-path times are fingerprints of multidimensionality of the underlying free energy landscapes

2020 ◽  
Vol 117 (44) ◽  
pp. 27116-27123 ◽  
Author(s):  
Rohit Satija ◽  
Alexander M. Berezhkovskii ◽  
Dmitrii E. Makarov
Keyword(s):  
Free Energy ◽  
Single Molecule ◽  
Coefficient Of Variation ◽  
Biological Membrane ◽  
Energy Landscape ◽  
Transition Path ◽  
Activation Barriers ◽  
One Dimensional ◽  
Dimensional Diffusion ◽  
Transition Paths

Recent single-molecule experiments have observed transition paths, i.e., brief events where molecules (particularly biomolecules) are caught in the act of surmounting activation barriers. Such measurements offer unprecedented mechanistic insights into the dynamics of biomolecular folding and binding, molecular machines, and biological membrane channels. A key challenge to these studies is to infer the complex details of the multidimensional energy landscape traversed by the transition paths from inherently low-dimensional experimental signals. A common minimalist model attempting to do so is that of one-dimensional diffusion along a reaction coordinate, yet its validity has been called into question. Here, we show that the distribution of the transition path time, which is a common experimental observable, can be used to differentiate between the dynamics described by models of one-dimensional diffusion from the dynamics in which multidimensionality is essential. Specifically, we prove that the coefficient of variation obtained from this distribution cannot possibly exceed 1 for any one-dimensional diffusive model, no matter how rugged its underlying free energy landscape is: In other words, this distribution cannot be broader than the single-exponential one. Thus, a coefficient of variation exceeding 1 is a fingerprint of multidimensional dynamics. Analysis of transition paths in atomistic simulations of proteins shows that this coefficient often exceeds 1, signifying essential multidimensionality of those systems.

scholarly journals Slow Transition Path Times Reveal a Complex Folding Barrier in a Designed Protein

2020 ◽  
Vol 8 ◽  
Author(s):  
Alexander Mehlich ◽  
Jie Fang ◽  
Benjamin Pelz ◽  
Hongbin Li ◽  
Johannes Stigler
Keyword(s):  
Optical Tweezers ◽  
Single Molecule ◽  
De Novo ◽  
High Energy ◽  
Transition Path ◽  
Barrier Crossing ◽  
Designed Proteins ◽  
Transition Barrier ◽  
Millisecond Range ◽  
Transition Times

De-novo designed proteins have received wide interest as potential platforms for nano-engineering and biomedicine. While much work is being done in the design of thermodynamically stable proteins, the folding process of artificially designed proteins is not well-studied. Here we used single-molecule force spectroscopy by optical tweezers to study the folding of ROSS, a de-novo designed 2x2 Rossmann fold. We measured a barrier crossing time in the millisecond range, much slower than what has been reported for other systems. While long transition times can be explained by barrier roughness or slow diffusion, we show that isotropic roughness cannot explain the measured transition path time distribution. Instead, this study shows that the slow barrier crossing of ROSS is caused by the population of three short-lived high-energy intermediates. In addition, we identify incomplete and off-pathway folding events with different barrier crossing dynamics. Our results hint at the presence of a complex transition barrier that may be a common feature of many artificially designed proteins.

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