title: Interfacial interaction and lateral association of cross-seeding assemblies between hIAPP and rIAPP oligomers.
abstract: Cross-sequence interactions between different amyloid peptides are important not only for the fundamental understanding of amyloid aggregation and polymorphism mechanisms, but also for probing a potential molecular link between different amyloid diseases. Here, we computationally modeled and simulated a series of hybrid hIAPP (human islet amyloid polypeptide)-rIAPP (rat islet amyloid polypeptide) assemblies and probed their structural stability, lateral association, and interfacial interactions using combined peptide-packing search, molecular dynamics (MD) simulations, and the Monte Carlo sampling method. We then identified a number of stable and highly populated hIAPP-rIAPP assemblies at the lowest energy states, in which hIAPP and rIAPP oligomers were stacked laterally on top of each other to form supramolecular β-sheet double layers in an antiparallel fashion. These hIAPP-rIAPP assemblies adopted different interfaces formed by C-terminal β-sheets of hIAPP and rIAPP oligomers (hCCr), N-terminal β-sheets of hIAPP and rIAPP oligomers (hNNr), and alternative N-terminal/C-terminal β-sheets of hIAPP and rIAPP oligomers (hNCr and hCNr). Different interfaces along with distinct interfacial residue packings provided different driving interfacial forces to laterally associate two β-sheet layers of hIAPP and rIAPP together for forming polymorphic hIAPP-rIAPP assemblies. Such lateral association between hIAPP and rIAPP not only explained the experimentally observed cross-seeding behavior of hIAPP and rIAPP, but also demonstrated the co-existence of polymorphic amyloid cross-seeding species. A cross-seeding mechanism for hIAPP and rIAPP aggregation was proposed on the basis of our simulated models and experimental data. This work provides a better understanding of cross-seeding aggregation and polymorphism mechanisms of amyloidogenesis.
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA. zhengj@uakron.edu.
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: Yung
authors.initials: Y
authors.lastname: Chang
authors.forename: Xiong
authors.initials: X
authors.lastname: Gong
authors.forename: Fufeng
authors.initials: F
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D051381:Rats
chemical_list: D058228:Islet Amyloid Polypeptide