UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology
Publication Date
2019-06-18
Document Type
Article
Disciplines
Amino Acids, Peptides, and Proteins | Biophysics | Computational Biology | Structural Biology
Abstract
Proteins are marginally stable molecules that fluctuate between folded and unfolded states. Here, we provide a high-resolution description of unfolded states under refolding conditions for the N-terminal domain of the L9 protein (NTL9). We use a combination of time-resolved Forster resonance energy transfer (FRET) based on multiple pairs of minimally perturbing labels, time-resolved small-angle X-ray scattering (SAXS), all-atom simulations, and polymer theory. Upon dilution from high denaturant, the unfolded state undergoes rapid contraction. Although this contraction occurs before the folding transition, the unfolded state remains considerably more expanded than the folded state and accommodates a range of local and nonlocal contacts, including secondary structures and native and nonnative interactions. Paradoxically, despite discernible sequence-specific conformational preferences, the ensemble-averaged properties of unfolded states are consistent with those of canonical random coils, namely polymers in indifferent (theta) solvents. These findings are concordant with theoretical predictions based on coarse-grained models and inferences drawn from single-molecule experiments regarding the sequence-specific scaling behavior of unfolded proteins under folding conditions.
Keywords
FRET, compaction transition, protein folding, unfolded state
Rights and Permissions
Copyright © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial- NoDerivatives License 4.0 (CC BY-NC-ND).
DOI of Published Version
10.1073/pnas.1818206116
Source
Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12301-12310. doi: 10.1073/pnas.1818206116. Epub 2019 Jun 5. Link to article on publisher's site
Journal/Book/Conference Title
Proceedings of the National Academy of Sciences of the United States of America
Related Resources
PubMed ID
31167941
Repository Citation
Peran I, Holehouse AS, Carrico IS, Pappu RV, Bilsel O, Raleigh DP. (2019). Unfolded states under folding conditions accommodate sequence-specific conformational preferences with random coil-like dimensions. Open Access Articles. https://doi.org/10.1073/pnas.1818206116. Retrieved from https://escholarship.umassmed.edu/oapubs/3900
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
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Amino Acids, Peptides, and Proteins Commons, Biophysics Commons, Computational Biology Commons, Structural Biology Commons