Markov State Model of ACBP analyzed in "Slow unfolded-state structuring in Acyl-CoA binding protein folding revealed by simulation and experiment".
Abstract/Contents
- Abstract
- Protein folding is a fundamental process in biology, key to understanding many human diseases. Experimentally, proteins often appear to fold via simple two- or three-state mechanisms involving mainly native-state interactions, yet recent network models built from atomistic simulations of small proteins suggest the existence of many possible metastable states and folding pathways. We reconcile these two pictures in a combined experimental and simulation study of acyl-coenzyme A binding protein (ACBP), a two-state folder (folding time ~10 ms) exhibiting residual unfolded-state structure, and a putative early folding intermediate. Using single-molecule FRET in conjunction with side-chain mutagenesis, we first demonstrate that the denatured state of ACBP at near-zero denaturant is unusually compact and enriched in long-range structure that can be perturbed by discrete hydrophobic core mutations. We then employ ultrafast laminar-flow mixing experiments to study the folding kinetics of ACBP on the microsecond time scale. These studies, along with Trp-Cys quenching measurements of unfolded-state dynamics, suggest that unfolded-state structure forms on a surprisingly slow (~100 μs) time scale, and that sequence mutations strikingly perturb both time-resolved and equilibrium smFRET measurements in a similar way. A Markov state model (MSM) of the ACBP folding reaction, constructed from over 30 ms of molecular dynamics trajectory data, predicts a complex network of metastable stables, residual unfolded-state structure, and kinetics consistent with experiment but no well-defined intermediate preceding the main folding barrier. Taken together, these experimental and simulation results suggest that the previously characterized fast kinetic phase is not due to formation of a barrier-limited intermediate but rather to a more heterogeneous and slow acquisition of unfolded-state structure.
Description
| Type of resource | software, multimedia |
|---|---|
| Date created | 2012 |
Creators/Contributors
| Author | Voelz, Vincent | |
|---|---|---|
| Principal investigator | Pande, Vijay | |
| Collector | Lane, Thomas |
Subjects
| Subject | ACBP |
|---|---|
| Subject | Markov State Model |
| Subject | protein folding |
| Genre | Dataset |
Bibliographic information
| Related Publication | Voelz VA, Jäger M, Yao S, Chen Y, Zhu L, Waldauer SA, Bowman GR, Friedrichs M, Bakajin O, Lapidus LJ, Weiss S, Pande VS. (2012). Slow unfolded-state structuring in Acyl-CoA binding protein folding revealed by simulation and experiment. J Am Chem Soc. 134(30):12565-77. doi: 10.1021/ja302528z |
|---|---|
| Related item | |
| Location | https://purl.stanford.edu/wt101ks3240 |
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- Use and reproduction
- User agrees that, where applicable, content will not be used to identify or to otherwise infringe the privacy or confidentiality rights of individuals. Content distributed via the Stanford Digital Repository may be subject to additional license and use restrictions applied by the depositor.
- License
- This work is licensed under a Creative Commons Attribution Share Alike 3.0 Unported license (CC BY-SA).
Collection
Folding@home Collection
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- Contact
- voelz@temple.edu
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