title: Polymorphic Associations and Structures of the Cross-Seeding of Aβ1-42 and hIAPP1-37 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.
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Zhang
authors.forename: Rundong
authors.initials: R
authors.lastname: Hu
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Xiong
authors.initials: X
authors.lastname: Gong
authors.affiliation: Department of Chemistry and Biochemistry, California State University, Los Angeles , Los Angeles, California 90032, United States.
authors.forename: Feimeng
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Geriatric Neurology, Nanjing Brain Hospital Affiliated to Nanjing Medical University , Nanjing, Jiangsu 210029, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000150:complications / Q000378:metabolism*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)