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Frustration Dynamics and Electron-Transfer Reorganization Energies in Wild-Type and Mutant Azurins

Chen, Xun and Chen, Mingchen and Wolynes, Peter G. and Wittung-Stafshede, Pernilla and Gray, Harry B. (2022) Frustration Dynamics and Electron-Transfer Reorganization Energies in Wild-Type and Mutant Azurins. Journal of the American Chemical Society, 144 (9). pp. 4178-4185. ISSN 0002-7863. PMCID PMC8915257. doi:10.1021/jacs.1c13454.

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Long-range electron tunneling through metalloproteins is facilitated by evolutionary tuning of donor–acceptor electronic couplings, formal electrochemical potentials, and active-site reorganization energies. Although the minimal frustration of the folding landscape enables this tuning, residual frustration in the vicinity of the metallocofactor can allow conformational fluctuations required for protein function. We show here that the constrained copper site in wild-type azurin is governed by an intricate pattern of minimally frustrated local and distant interactions that together enable rapid electron flow to and from the protein. In contrast, sluggish electron transfer reactions (unfavorable reorganization energies) of active-site azurin variants are attributable to increased frustration near to as well as distant from the copper site, along with an exaggerated oxidation-state dependence of both minimally and highly frustrated interaction patterns.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle Iteminput files and data/frustration analysis code
Chen, Xun0000-0002-0601-8397
Chen, Mingchen0000-0003-3916-7871
Wolynes, Peter G.0000-0001-7975-9287
Wittung-Stafshede, Pernilla0000-0003-1058-1964
Gray, Harry B.0000-0002-7937-7876
Additional Information:© 2022 The Authors. Published by American Chemical Society. Attribution 4.0 International (CC BY 4.0). Received 21 December 2021. Published online 16 February 2022. This work was funded by the Center for Theoretical Biological Physics, sponsored by NSF grant PHY-2019745. Support was also provided by the D.R. Bullard-Welch Chair at Rice University, Grant C-0016. We thank the Data Analysis and Visualization Cyberinfrastructure funded by the National Science Foundation Grant OCI-0959097. Work at Caltech (H.B.G.) was supported by the Arnold and Mabel Beckman Foundation and by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number R01DK019038. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. P.W.S. acknowledges funding from the Swedish Research Council and the Knut and Alice Wallenberg Foundation. The authors declare no competing financial interest. The input files and data from the frustration analysis in this work are deposited in GitHub: The frustration analysis codes in this work are deposited in GitHub:
Funding AgencyGrant Number
Rice UniversityC-0016
Arnold and Mabel Beckman FoundationUNSPECIFIED
Swedish Research CouncilUNSPECIFIED
Knut and Alice Wallenberg FoundationUNSPECIFIED
Subject Keywords:Copper, Crystal structure, Protein structure, Electrical energy, Energy
Issue or Number:9
PubMed Central ID:PMC8915257
Record Number:CaltechAUTHORS:20220217-687014000
Persistent URL:
Official Citation:Frustration Dynamics and Electron-Transfer Reorganization Energies in Wild-Type and Mutant Azurins. Xun Chen, Mingchen Chen, Peter G. Wolynes, Pernilla Wittung-Stafshede, and Harry B. Gray. Journal of the American Chemical Society 2022 144 (9), 4178-4185; DOI: 10.1021/jacs.1c13454
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:113492
Deposited By: George Porter
Deposited On:17 Feb 2022 21:11
Last Modified:18 Mar 2022 16:46

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