Dear, Alexander J.; Šarić, AnđelaISTA ; Michaels, Thomas C. T.; Dobson, Christopher M.; Knowles, Tuomas P. J.
The misfolding and aggregation of proteins into linear fibrils is widespread in human biology, for example, in connection with amyloid formation and the pathology of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. The oligomeric species that are formed in the early stages of protein aggregation are of great interest, having been linked with the cellular toxicity associated with these conditions. However, these species are not characterized in any detail experimentally, and their properties are not well understood. Many of these species have been found to have approximately spherical morphology and to be held together by hydrophobic interactions. We present here an analytical statistical mechanical model of globular oligomer formation from simple idealized amphiphilic protein monomers and show that this correlates well with Monte Carlo simulations of oligomer formation. We identify the controlling parameters of the model, which are closely related to simple quantities that may be fitted directly from experiment. We predict that globular oligomers are unlikely to form at equilibrium in many polypeptide systems but instead form transiently in the early stages of amyloid formation. We contrast the globular model of oligomer formation to a well-established model of linear oligomer formation, highlighting how the differing ensemble properties of linear and globular oligomers offer a potential strategy for characterizing oligomers from experimental measurements.
The Journal of Physical Chemistry B
We acknowledge support from the Schiff Foundation (A.J.D.), the Royal Society (A.Š.), the Academy of Medical Sciences and Wellcome Trust (A.Š.), Peterhouse, Cambridge (T.C.T.M.), the Swiss National Science foundation (T.C.T.M.), the Wellcome Trust (T.P.J.K.), the Cambridge Centre for Misfolding Diseases (T.P.J.K.), the BBSRC (T.P.J.K.), the Frances and Augustus Newman foundation (T.P.J.K.). The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (Grant FP7/2007-2013) through the ERC Grant PhysProt (Agreement No. 337969). We thank Daan Frenkel for several useful discussions.
Dear AJ, Šarić A, Michaels TCT, Dobson CM, Knowles TPJ. Statistical mechanics of globular oligomer formation by protein molecules. The Journal of Physical Chemistry B. 2018;122(49):11721-11730. doi:10.1021/acs.jpcb.8b07805
Dear, A. J., Šarić, A., Michaels, T. C. T., Dobson, C. M., & Knowles, T. P. J. (2018). Statistical mechanics of globular oligomer formation by protein molecules. The Journal of Physical Chemistry B. American Chemical Society. https://doi.org/10.1021/acs.jpcb.8b07805
Dear, Alexander J., Anđela Šarić, Thomas C. T. Michaels, Christopher M. Dobson, and Tuomas P. J. Knowles. “Statistical Mechanics of Globular Oligomer Formation by Protein Molecules.” The Journal of Physical Chemistry B. American Chemical Society, 2018. https://doi.org/10.1021/acs.jpcb.8b07805.
A. J. Dear, A. Šarić, T. C. T. Michaels, C. M. Dobson, and T. P. J. Knowles, “Statistical mechanics of globular oligomer formation by protein molecules,” The Journal of Physical Chemistry B, vol. 122, no. 49. American Chemical Society, pp. 11721–11730, 2018.
Dear AJ, Šarić A, Michaels TCT, Dobson CM, Knowles TPJ. 2018. Statistical mechanics of globular oligomer formation by protein molecules. The Journal of Physical Chemistry B. 122(49), 11721–11730.
Dear, Alexander J., et al. “Statistical Mechanics of Globular Oligomer Formation by Protein Molecules.” The Journal of Physical Chemistry B, vol. 122, no. 49, American Chemical Society, 2018, pp. 11721–30, doi:10.1021/acs.jpcb.8b07805.