title: In silico cross seeding of Aβ and amylin fibril-like oligomers.
abstract: Recent epidemiological data have shown that patients suffering from Type 2 Diabetes Mellitus have an increased risk to develop Alzheimer's disease and vice versa. A possible explanation is the cross-sequence interaction between Aβ and amylin. Because the resulting amyloid oligomers are difficult to probe in experiments, we investigate stability and conformational changes of Aβ-amylin heteroassemblies through molecular dynamics simulations. We find that Aβ is a good template for the growth of amylin and vice versa. We see water molecules permeate the β-strand-turn-β-strand motif pore of the oligomers, supporting a commonly accepted mechanism for toxicity of β-rich amyloid oligomers. Aiming for a better understanding of the physical mechanisms of cross-seeding and cell toxicity of amylin and Aβ aggregates, our simulations also allow us to identify targets for the rational design of inhibitors against toxic fibril-like oligomers of Aβ and amylin oligomers.
authors.affiliation: Department of Chemistry & Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
authors.forename: Workalemahu M
authors.initials: WM
authors.lastname: Berhanu
authors.forename: Fatih
authors.initials: F
authors.lastname: Yaşar
authors.forename: Ulrich H E
authors.initials: UH
authors.lastname: Hansmann
mesh_terms: D020816:Amino Acid Motifs / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000009:adverse effects* / Q000096:biosynthesis / Q000737:chemistry; D002463:Cell Membrane Permeability / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D058228:Islet Amyloid Polypeptide / Q000009:adverse effects* / Q000096:biosynthesis / Q000737:chemistry; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D016874:Neurofibrillary Tangles / Q000737:chemistry* / Q000187:drug effects / Q000473:pathology; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D016875:tau Proteins