Protein aggregation into amyloid fibrils is the archetype of aberrant biomolecular self\u0002assembly processes, with more than 50 associated diseases that are mostly uncurable.
Understanding aggregation mechanisms is thus of fundamental importance and goes in
parallel with the structural characterization of the transient oligomers formed during
the process. Oligomers have been proven elusive to high-resolution structural techni\u0002ques, while the large sizes and long time scales, typical of aggregation processes, have
limited the use of computational methods to date. To surmount these limitations, we
here present multi-eGO, an atomistic, hybrid structure-based model which, leveraging
the knowledge of monomers conformational dynamics and of fibril structures, effi\u0002ciently captures the essential structural and kinetics aspects of protein aggregation.
Multi-eGO molecular dynamics simulations can describe the aggregation kinetics of
thousands of monomers. The concentration dependence of the simulated kinetics, as
well as the structural features of the resulting fibrils, are in qualitative agreement with
in vitro experiments carried out on an amyloidogenic peptide from Transthyretin, a
protein responsible for one of the most common cardiac amyloidoses. Multi-eGO simu\u0002lations allow the formation of primary nuclei in a sea of transient lower-order oligomers
to be observed over time and at atomic resolution, following their growth and the sub\u0002sequent secondary nucleation events, until the maturation of multiple fibrils is achieved.
Multi-eGO, combined with the many experimental techniques deployed to study pro\u0002tein aggregation, can provide the structural basis needed to advance the design of mole\u0002cules targeting amyloidogenic diseases<\/p>\n\n\n\n
PNAS 2022 Vol. 119 No. 26 e2203181119<\/p>\n\n\n\n