Driving protein conformational cycles in physiology and disease: “Frustrated” amino acid interaction networks define dynamic energy landscapes

We propose a general framework by which dynamic interactions within a protein will promote the necessary series of structural changes, or “conformational cycle”, required for function. We suggest that the free energy landscape of a protein is biased towards this conformational cycle. Fluctuations into higher energy, albeit thermally accessible, conformations drive the conformational cycle forward. The amino acid interaction network is defined as those intra-protein interactions that contribute most to the free energy landscape. Some network connections are consistent in every structural state, while others periodically change their interaction strength according to the conformational cycle. As we review here, structural transitions change these periodic network connections, which then predisposes the protein towards the next set of network changes, and hence the next structural change. These concepts are illustrated by our recent work on tryptophan synthase. Disruption of these dynamic connections may lead to aberrant protein function and disease states.

This is the peer reviewed version of the following article: [D’Amico, R.N., Murray, A.M., and Boehr, D.D. (2020). Driving Protein Conformational Cycles in Physiology and Disease: “Frustrated” Amino Acid Interaction Networks Define Dynamic Energy Landscapes. BioEssays 42, 2000092.], which has been published in final form at https://doi.org/10.1002/bies.202000092. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions: https://authorservices.wiley.com/author-resources/Journal-Authors/licensing/self-archiving.html#3.

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Work Title Driving protein conformational cycles in physiology and disease: “Frustrated” amino acid interaction networks define dynamic energy landscapes
Access
Open Access
Creators
  1. Rebecca Noel D'Amico
  2. Alec Michael Murray
  3. David Boehr
Keyword
  1. allosteric network
  2. allostery
  3. catalytic cycle
License In Copyright (Rights Reserved)
Work Type Article
Publisher
  1. BioEssays
Publication Date July 27, 2020
Publisher Identifier (DOI)
  1. 10.1002/bies.202000092
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Deposited February 24, 2021

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  • Added Creator David Boehr
  • Added Creator Rebecca Noel D'Amico
  • Added Creator Alec Michael Murray
  • Added DAmicoBoehr-revised.docx
  • Updated License Show Changes
    License
    • https://rightsstatements.org/page/InC/1.0/
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Version 2
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  • Created
  • Updated Keyword, Publisher, Publisher Identifier (DOI), and 2 more Show Changes
    Keyword
    • allosteric network, allostery, catalytic cycle
    Publisher
    • BioEssays
    Publisher Identifier (DOI)
    • 10.1002/bies.202000092
    Description
    • We propose a general framework by which dynamic interactions within a protein will promote the necessary series of structural changes, or “conformational cycle”, required for function. We suggest that the free energy landscape of a protein is biased towards this conformational cycle. Fluctuations into higher energy, albeit thermally accessible, conformations drive the conformational cycle forward. The amino acid interaction network is defined as those intra-protein interactions that contribute most to the free energy landscape. Some network connections are consistent in every structural state, while others periodically change their interaction strength according to the conformational cycle. As we review here, structural transitions change these periodic network connections, which then predisposes the protein towards the next set of network changes, and hence the next structural change. These concepts are illustrated by our recent work on tryptophan synthase. Disruption of these dynamic connections may lead to aberrant protein function and disease states.
    • We propose a general framework by which dynamic interactions within a protein will promote the necessary series of structural changes, or “conformational cycle”, required for function. We suggest that the free energy landscape of a protein is biased towards this conformational cycle. Fluctuations into higher energy, albeit thermally accessible, conformations drive the conformational cycle forward. The amino acid interaction network is defined as those intra-protein interactions that contribute most to the free energy landscape. Some network connections are consistent in every structural state, while others periodically change their interaction strength according to the conformational cycle. As we review here, structural transitions change these periodic network connections, which then predisposes the protein towards the next set of network changes, and hence the next structural change. These concepts are illustrated by our recent work on tryptophan synthase. Disruption of these dynamic connections may lead to aberrant protein function and disease states.
    • This is the peer reviewed version of the following article: [D’Amico, R.N., Murray, A.M., and Boehr, D.D. (2020). Driving Protein Conformational Cycles in Physiology and Disease: “Frustrated” Amino Acid Interaction Networks Define Dynamic Energy Landscapes. BioEssays 42, 2000092.], which has been published in final form at https://doi.org/10.1002/bies.202000092. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions: https://authorservices.wiley.com/author-resources/Journal-Authors/licensing/self-archiving.html#3.
    Related URLs
    • https://doi.org/10.1002/bies.202000092
  • Updated Creator Rebecca Noel D'Amico
  • Updated Creator David Boehr
  • Updated Creator Alec Michael Murray
  • Deleted DAmicoBoehr-revised.docx
  • Added DAmicoBoehr-revised.pdf
  • Published
  • Updated