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Allostery and Kinetic Proofreading

Galstyan, Vahe and Phillips, Rob (2019) Allostery and Kinetic Proofreading. Journal of Physical Chemistry B, 123 (51). pp. 10990-11002. ISSN 1520-6106. PMCID PMC6995354. https://resolver.caltech.edu/CaltechAUTHORS:20191202-151154014

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Abstract

Kinetic proofreading is an error correction mechanism present in the processes of the central dogma and beyond and typically requires the free energy of nucleotide hydrolysis for its operation. Though the molecular players of many biological proofreading schemes are known, our understanding of how energy consumption is managed to promote fidelity remains incomplete. In our work, we introduce an alternative conceptual scheme called “the piston model of proofreading” in which enzyme activation through hydrolysis is replaced with allosteric activation achieved through mechanical work performed by a piston on regulatory ligands. Inspired by Feynman’s ratchet and pawl mechanism, we consider a mechanical engine designed to drive the piston actions powered by a lowering weight, whose function is analogous to that of ATP synthase in cells. Thanks to its mechanical design, the piston model allows us to tune the “knobs” of the driving engine and probe the graded changes and trade-offs between speed, fidelity, and energy dissipation. It provides an intuitive explanation of the conditions necessary for optimal proofreading and reveals the unexpected capability of allosteric molecules to beat the Hopfield limit of fidelity by leveraging the diversity of states available to them. The framework that we have built for the piston model can also serve as a basis for additional studies of driven biochemical systems.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acs.jpcb.9b08380DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6995354/PubMed CentralArticle
ORCID:
AuthorORCID
Galstyan, Vahe0000-0001-7073-9175
Phillips, Rob0000-0003-3082-2809
Additional Information:© 2019 American Chemical Society. Received: September 3, 2019; Revised: November 21, 2019; Published: November 28, 2019. We thank Tal Einav, Erwin Frey, Christina Hueschen, Sarah Marzen, Arvind Murugan, Manuel Razo-Mejia, Matt Thomson, Yuhai Tu, Jin Wang, Jerry Wang, Ned Wingreen, and Fangzhou Xiao for fruitful discussions. We also thank Haojie Li and Dennis Yatunin for their input on this work, Alexander Grosberg, David Sivak, and Pablo Sartori for providing valuable feedback on the manuscript, and Nigel Orme for his assistance in making the illustrations. This work was supported by the National Institutes of Health through Grant 1R35 GM118043-01 (MIRA) and the John Templeton Foundation as part of the Boundaries of Life Initiative (Grants 51250 and 60973). The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
NIH1R35 GM118043-01
John Templeton Foundation51250
John Templeton Foundation60973
Issue or Number:51
PubMed Central ID:PMC6995354
Record Number:CaltechAUTHORS:20191202-151154014
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191202-151154014
Official Citation:Allostery and Kinetic Proofreading. Vahe Galstyan and Rob Phillips. The Journal of Physical Chemistry B 2019 123 (51), 10990-11002. DOI: 10.1021/acs.jpcb.9b08380
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100149
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:04 Dec 2019 18:37
Last Modified:07 May 2020 21:52

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