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Title: Frustration and folding of a TIM barrel protein

Abstract

Triosephosphate isomerase (TIM) barrel proteins have not only a conserved architecture that supports a myriad of enzymatic functions, but also a conserved folding mechanism that involves on- and off-pathway intermediates. Although experiments have proven to be invaluable in defining the folding free-energy surface, they provide only a limited understanding of the structures of the partially folded states that appear during folding. Coarse-grained simulations employing native centric models are capable of sampling the entire energy landscape of TIM barrels and offer the possibility of a molecular-level understanding of the readout from sequence to structure. In this work, we have combined sequence-sensitive native centric simulations with small-angle X-ray scattering and time-resolved Förster resonance energy transfer to monitor the formation of structure in an intermediate in the Sulfolobus solfataricus indole-3-glycerol phosphate synthase TIM barrel that appears within 50 μs and must at least partially unfold to achieve productive folding. Simulations reveal the presence of a major and 2 minor folding channels not detected in experiments. Frustration in folding, i.e., backtracking in native contacts, is observed in the major channel at the initial stage of folding, as well as late in folding in a minor channel before the appearance of the native conformation. Similaritiesmore » in global and pairwise dimensions of the early intermediate, the formation of structure in the central region that spreads progressively toward each terminus, and a similar rate-limiting step in the closing of the β-barrel underscore the value of combining simulation and experiment to unravel complex folding mechanisms at the molecular level.« less

Authors:
 [1];  [2];  [2];  [3];  [3];  [1]; ORCiD logo [2];  [1]
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  1. Univ. of Massachusetts Medical School, Worcester, MA (United States)
  2. Univ. of Michigan, Ann Arbor, MI (United States)
  3. Illinois Inst. of Technology, Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institute of General Medical Sciences (NIGMS); National Science Foundation (NSF); USDOE Office of Science (SC); National Institutes of Health (NIH)
OSTI Identifier:
1557323
Grant/Contract Number:  
5 R01 GM023303; 1353942; AC02-06CH11357; 9 P41 GM103622; 1S10OD018090-01
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 116; Journal Issue: 33; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; protein-folding intermediates; Go models; TIM barrel protein

Citation Formats

Halloran, Kevin T., Wang, Yanming, Arora, Karunesh, Chakravarthy, Srinivas, Irving, Thomas C., Bilsel, Osman, Brooks III, Charles L., and Matthews, C. Robert. Frustration and folding of a TIM barrel protein. United States: N. p., 2019. Web. doi:10.1073/pnas.1900880116.
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Halloran, Kevin T., Wang, Yanming, Arora, Karunesh, Chakravarthy, Srinivas, Irving, Thomas C., Bilsel, Osman, Brooks III, Charles L., & Matthews, C. Robert. Frustration and folding of a TIM barrel protein. United States. https://doi.org/10.1073/pnas.1900880116
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Halloran, Kevin T., Wang, Yanming, Arora, Karunesh, Chakravarthy, Srinivas, Irving, Thomas C., Bilsel, Osman, Brooks III, Charles L., and Matthews, C. Robert. Thu . "Frustration and folding of a TIM barrel protein". United States. https://doi.org/10.1073/pnas.1900880116. https://www.osti.gov/servlets/purl/1557323.
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@article{osti_1557323,
title = {Frustration and folding of a TIM barrel protein},
author = {Halloran, Kevin T. and Wang, Yanming and Arora, Karunesh and Chakravarthy, Srinivas and Irving, Thomas C. and Bilsel, Osman and Brooks III, Charles L. and Matthews, C. Robert},
abstractNote = {Triosephosphate isomerase (TIM) barrel proteins have not only a conserved architecture that supports a myriad of enzymatic functions, but also a conserved folding mechanism that involves on- and off-pathway intermediates. Although experiments have proven to be invaluable in defining the folding free-energy surface, they provide only a limited understanding of the structures of the partially folded states that appear during folding. Coarse-grained simulations employing native centric models are capable of sampling the entire energy landscape of TIM barrels and offer the possibility of a molecular-level understanding of the readout from sequence to structure. In this work, we have combined sequence-sensitive native centric simulations with small-angle X-ray scattering and time-resolved Förster resonance energy transfer to monitor the formation of structure in an intermediate in the Sulfolobus solfataricus indole-3-glycerol phosphate synthase TIM barrel that appears within 50 μs and must at least partially unfold to achieve productive folding. Simulations reveal the presence of a major and 2 minor folding channels not detected in experiments. Frustration in folding, i.e., backtracking in native contacts, is observed in the major channel at the initial stage of folding, as well as late in folding in a minor channel before the appearance of the native conformation. Similarities in global and pairwise dimensions of the early intermediate, the formation of structure in the central region that spreads progressively toward each terminus, and a similar rate-limiting step in the closing of the β-barrel underscore the value of combining simulation and experiment to unravel complex folding mechanisms at the molecular level.},
doi = {10.1073/pnas.1900880116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 33,
volume = 116,
place = {United States},
year = {Thu Jul 25 00:00:00 EDT 2019},
month = {Thu Jul 25 00:00:00 EDT 2019}
}
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https://doi.org/10.1073/pnas.1900880116
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    journal, January 2020

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    • Journal of Biological Chemistry, Vol. 295, Issue 1
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