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Statistical Mechanics of Globular Oligomer Formation by Protein Molecules
journal contribution
posted on 2018-10-18, 00:00 authored by Alexander
J. Dear, Anđela Šarić, Thomas C. T. Michaels, Christopher M. Dobson, Tuomas P. J. KnowlesThe
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.