Polymorphic Associations and Structures of the Cross-Seeding of Aβ_1–42 and hIAPP_1–37 Polypeptides

Abstract

Emerging evidence have shown that the patients with Alzheimer's disease (AD) often have a higher risk of later developing type II diabetes (T2D), and vice versa, suggesting a potential pathological link between AD and T2D. Amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) are the principle causative components responsible for the pathologies of AD and T2D, respectively. The cross-sequence interactions between Aβ and hIAPP may provide a molecular basis for better understanding the potential link between AD and T2D. Herein, we systematically modeled and simulated the cross-sequence aggregation process, molecular interactions, and polymorphic structures of full-length Aβ and hIAPP peptides using a combination of coarse-grained (CG) replica-exchange molecular dynamics (REMD) and all-atom molecular dynamics (MD) simulations, with particular focus on the effect of association models between Aβ and hIAPP on the structural stability and polymorphic populations of hybrid Aβ-hIAPP aggregates. Four distinct association models (double-layer, elongation, tail-tail, and block models) between Aβ and hIAPP oligomers were identified, and the associated polymorphic Aβ-hIAPP structures were determined as well. Among them, different association models led to different Aβ-hIAPP aggregates, with large differences in structural morphologies and populations, interacting interfaces, and underlying association forces. The computational models support the cross-sequence interactions between Aβ and hIAPP pentamers, which would lead to the complex hybrid Aβ-hIAPP assemblies. This computational work may also provide a different point of view to a better understanding of a potential link between AD and T2D.

Experimental and Computational Protocols for Studies of Cross-Seeding Amyloid Assemblies

“…First, 500 structures per each all-atom Aβ-hIAPP model are extracted from the last 10-ns explicit-water MD trajectories, excluding water molecules [30]. …”

Brazilin inhibits fibrillogenesis of human islet amyloid polypeptide, disassembles mature fibrils, and alleviates cytotoxicity

“…Importantly, some of these residues, such as Arg11, Phe15 and Ser19, were reported to play an important role in the self-assembly of hIAPP. 76,77 Within the N-terminal region, the six residues Asn3, Thr4, Thr9, Arg11, Asn14 and Phe15 were identied as being important. Fig.…”

Characterisation of the Structure and Oligomerisation of Islet Amyloid Polypeptides (IAPP): A Review of Molecular Dynamics Simulation Studies

“…A coarse-grained (CG)-based REMD simulation study using the Martini force field followed by all-atom simulations using the CHARMM27 force field with the CMAP correction and the SPC/E water model characterised the cross-seeding between the pentamers of Aβ 42 and hIAPP, whose structure were taken from fibrils [ 40 , 130 ]. These pentameric structures were determined to interact in various preferred orientations: double-layer model (43%), elongation model (30%), tail-tail model (21%) and block model (7%) ( Figure 21 ) [ 131 ].…”

“… Structural ensemble of hetero-pentamers of Aβ 42 -hIAPP, showing their relative proportion and free energies for their mutual orientations. Adapted from Zhang et al [ 131 ]. Copyright 2015 American Chemical Society.…”