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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 ISSN 1553-7358.
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Official URL: https://doi.org/10.1371/journal.pcbi.1007919
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 | ||||||||||||||||||
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| Subjects: | Q Science > QP Physiology | ||||||||||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > 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: |
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| 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 (Creative Commons) | ||||||||||||||||||
| Date of first compliant deposit: | 27 July 2020 | ||||||||||||||||||
| Date of first compliant Open Access: | 27 July 2020 | ||||||||||||||||||
| RIOXX Funder/Project Grant: |
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