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Atomistic mechanism of transmembrane helix association

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Domański, Jan, Sansom, Mark S. P., Stansfeld, Phillip J. and Best, Robert B. (2020) Atomistic mechanism of transmembrane helix association. PLOS Computational Biology, 16 (6). e1007919. doi:10.1371/journal.pcbi.1007919

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Official URL: https://doi.org/10.1371/journal.pcbi.1007919

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Abstract

Transmembrane helix association is a fundamental step in the folding of helical membrane proteins. The prototypical example of this association is formation of the glycophorin dimer. While its structure and stability have been well-characterized experimentally, the detailed assembly mechanism is harder to obtain. Here, we use all-atom simulations within phospholipid membrane to study glycophorin association. We find that initial association results in the formation of a non-native intermediate, separated by a significant free energy barrier from the dimer with a native binding interface. We have used transition-path sampling to determine the association mechanism. We find that the mechanism of the initial bimolecular association to form the intermediate state can be mediated by many possible contacts, but seems to be particularly favoured by formation of non-native contacts between the C-termini of the two helices. On the other hand, the contacts which are key to determining progression from the intermediate to the native state are those which define the native binding interface, reminiscent of the role played by native contacts in determining folding of globular proteins. As a check on the simulations, we have computed association and dissociation rates from the transition-path sampling. We obtain results in reasonable accord with available experimental data, after correcting for differences in native state stability. Our results yield an atomistic description of the mechanism for a simple prototype of helical membrane protein folding.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
Divisions: Faculty of Science > Life Sciences (2010- )
SWORD Depositor: Library Publications Router
Library of Congress Subject Headings (LCSH): Membrane proteins , Glycoproteins , Protein folding
Journal or Publication Title: PLOS Computational Biology
Publisher: Public Library of Science
ISSN: 1553-7358
Official Date: 4 June 2020
Dates:
DateEvent
4 June 2020Published
30 April 2020Accepted
Date of first compliant deposit: 27 July 2020
Volume: 16
Number: 6
Article Number: e1007919
DOI: 10.1371/journal.pcbi.1007919
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
WT100946AIAWellcome Trusthttp://dx.doi.org/10.13039/100010269
WT100946AIANational Institutes of Healthhttp://dx.doi.org/10.13039/100000002
UNSPECIFIED[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
UNSPECIFIED[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
UNSPECIFIED[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
Related URLs:
  • https://creativecommons.org/publicdomain...
Contributors:
ContributionNameContributor ID
UNSPECIFIEDKasson, Peter MUNSPECIFIED

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