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Physical determinants of the self-replication of protein fibrils

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.

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Figure 1: The coarse-grained model and the nucleation processes in the system.
Figure 2: Conditions supporting fibril self-replication.
Figure 3: Strong bounds for self-replication.
Figure 4: Kinetics of fibril self-replication.
Figure 5: The reaction order is controlled by the surface saturation.

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Acknowledgements

We acknowledge support from the Human Frontier Science Program and Emmanuel College (A.Š.), the Leverhulme Trust and Magdalene College (A.K.B.), St John’s College (T.C.T.M.), the Biotechnology and Biological Sciences Research Council (T.P.J.K. and C.M.D.), the Frances and Augustus Newman Foundation (T.P.J.K.), the European Research Council (T.P.J.K., T.C.T.M., S.L. and D.F.), and the Engineering and Physical Sciences Research Council (D.F.).

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Contributions

A.Š., T.P.J.K. and D.F. conceived the project; A.Š. designed and performed the computer simulations; A.K.B. performed the SPR measurements; G.M. performed the kinetic analysis; T.C.T.M. and S.L. contributed materials and/or analysis tools, and all authors participated in interpreting the results and writing the paper.

Corresponding authors

Correspondence to Anđela Šarić or Tuomas P. J. Knowles.

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The authors declare no competing financial interests.

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Šarić, A., Buell, A., Meisl, G. et al. Physical determinants of the self-replication of protein fibrils. Nature Phys 12, 874–880 (2016). https://doi.org/10.1038/nphys3828

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