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Physical determinants of the self-replication of protein fibrils

Saric, A; Buell, AK; Meisl, G; Michaels, TCT; Dobson, CM; Linse, S; Knowles, TPJ; (2016) Physical determinants of the self-replication of protein fibrils. Nature Physics , 12 (9) pp. 874-880. 10.1038/NPHYS3828. Green open access

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Abstract

The ability of biological molecules to replicate themselves is the foundation of life, requiring a complex cellular machinery. However, a range of aberrant processes involve the self-replication of pathological protein structures without any additional assistance. One example is the autocatalytic generation of pathological protein aggregates, including amyloid fibrils, involved in neurodegenerative disorders. Here, we use computer simulations to identify the necessary requirements for the self-replication of fibrillar assemblies of proteins. We establish that a key physical determinant for this process is the affinity of proteins for the surfaces of fibrils. We find that self-replication can take place only in a very narrow regime of inter-protein interactions, implying a high level of sensitivity to system parameters and experimental conditions. We then compare our theoretical predictions with kinetic and biosensor measurements of fibrils formed from the Aβ peptide associated with Alzheimer’s disease. Our results show a quantitative connection between the kinetics of self-replication and the surface coverage of fibrils by monomeric proteins. These findings reveal the fundamental physical requirements for the formation of supra-molecular structures able to replicate themselves, and shed light on mechanisms in play in the proliferation of protein aggregates in nature.

Type: Article
Title: Physical determinants of the self-replication of protein fibrils
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/NPHYS3828
Publisher version: http://dx.doi.org/10.1038/NPHYS3828
Language: English
Additional information: Copyright © Macmillan Publishers 2016.
Keywords: Biological physics, Computational biophysics, Statistical mechanics, Statistical physics, Supramolecular assembly
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Physics and Astronomy
URI: https://discovery.ucl.ac.uk/id/eprint/1517406
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