Fitzpatrick, AW;
Knowles, TP;
Waudby, CA;
Vendruscolo, M;
Dobson, CM;
(2011)
Inversion of the balance between hydrophobic and hydrogen bonding interactions in protein folding and aggregation.
PLoS Comput Biol
, 7
(10)
, Article e1002169. 10.1371/journal.pcbi.1002169.
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Abstract
Identifying the forces that drive proteins to misfold and aggregate, rather than to fold into their functional states, is fundamental to our understanding of living systems and to our ability to combat protein deposition disorders such as Alzheimer's disease and the spongiform encephalopathies. We report here the finding that the balance between hydrophobic and hydrogen bonding interactions is different for proteins in the processes of folding to their native states and misfolding to the alternative amyloid structures. We find that the minima of the protein free energy landscape for folding and misfolding tend to be respectively dominated by hydrophobic and by hydrogen bonding interactions. These results characterise the nature of the interactions that determine the competition between folding and misfolding of proteins by revealing that the stability of native proteins is primarily determined by hydrophobic interactions between side-chains, while the stability of amyloid fibrils depends more on backbone intermolecular hydrogen bonding interactions.
| Type: | Article |
|---|---|
| Title: | Inversion of the balance between hydrophobic and hydrogen bonding interactions in protein folding and aggregation. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pcbi.1002169 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pcbi.1002169 |
| Language: | English |
| Additional information: | © 2011 Fitzpatrick et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from BBSRC (AWF, MV, CMD), the Royal Society (MV) and the Wellcome Trust (CMD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | Alzheimer Disease, Diabetes Mellitus, Type 2, Humans, Hydrogen Bonding, Parkinson Disease, Protein Folding |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1329705 |
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