Multiscale Aggregation of the Amyloid Aβ_16–22 Peptide: From Disordered Coagulation and Lateral Branching to Amorphous Prefibrils

Abstract

In this work we investigate the multiscale dynamics of the aggregation process of an amyloid peptide, Aβ16–22. By performing massive coarse-grained simulations at the quasi-atomistic resolution and including hydrodynamic effects, we followed the formation and growth of a large elongated aggregate and its slow structuring. The elongation proceeds via a two-step nucleation mechanism with disordered aggregates formed initially and subsequently fusing to elongate the amorphous prefibril. A variety of coagulation events coexist, including lateral growth. The latter mechanism, sustained by long-range hydrodynamics correlations, actually can create a large branched structure spanning a few tens of nanometers. Our findings confirm the experimental hypothesis of a critical contribution of lateral growth to the amyloid aggregation kinetics and the capability of our model to sample critical structures like prefibril hosting annular pores.

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…363 The second compromise concerns the effective concentration that is used in simulations 364 and that can be tuned so to favour the encounter of the molecules when the kinetics of aggregation and elongation is investigated. Finally, even with these simplifications in hands the size of the simulated systems is generally limited, generally with less than 10 3 monomers 365,366 .…”

“…Thanks to the simulation of a very large system, a complementary view to the one monomer addition was explored. It was possible to probe that at large length-scale once the first oligomers are formed, multiple fusion events take place to elongate the protofibril with not clear dominant scheme, 365,366 and including lateral branching that use the surface of the growing fibril as a seed. 366,383 This finding confirms the theoretical intuition proposed to describe the kinetics of amyloid formation, and that includes a key secondary nucleation process.…”

“…It was possible to probe that at large length-scale once the first oligomers are formed, multiple fusion events take place to elongate the protofibril with not clear dominant scheme, 365,366 and including lateral branching that use the surface of the growing fibril as a seed. 366,383 This finding confirms the theoretical intuition proposed to describe the kinetics of amyloid formation, and that includes a key secondary nucleation process. 309,384 When using implicit solvent CG models to explore protein aggregation two issues must alert the reader.…”

“…Panel D: Effect of hydrodynamic interactions on the aggregation process of Aβ16-22 peptides (left) and protofibril elongation due to oligomer fusion (right) as observed in LBMD simulations. 366,394 The authors designed panel A, panels C and D are updated from 366, 375 and 394 . Panel B was taken from 370 .…”

Aggregation of disease-related peptides

“…The aggregation process of Aβ16-22 was further investigated by considering a system of much larger size, 1000 peptides placed in a box of L=300 Å, corresponding to a concentration of 60 mM. 77 Using atomistic and explicit solvent, this system would count for 2.7 millions of particles, becoming prohibitive for classical MD simulations. The aggregation process was followed at the microsecond time scale, and for the first time three different regimes were clearly individuated.…”