Amyloid aggregation have been implicated in the pathology of many neurodegenerative diseases, including prion disease, Alzheimer's disease (AD), type II diabetes (T2D), and Parkinson disease. Amyloid peptides undergo the nucleation-polymerization aggregation process, during which amyloid peptides experience structural conversions from unstructured monomers to critical nucleus, and eventually to amyloid fibrils containing dominant ß-sheet structures. Such common misfolding and aggregation characteristics, in some cases, drive cross-seeding interactions between amyloid peptides, which play a major role in the progression and transmission between the neurodegenerative diseases. In the experiments, the cross-seeding interactions between amyloid peptides including ß-amyloid (Aß)-islet amyloid peptides (IAPP), Aß-tau, Aß-prion, human IAPP-rat IAPP, and tau-synuclein amyloids have been extensively implicated. However, high-resolution evidence is still unavailable and little is known about how these two peptides interact with each other.
In our research, we perform the multiscale molecular simulations to sysmetically study the cross-seeding interactions between different amyloid peptides at the atomic resolution, with the particular focus on the prediction of the atomic structures, the dynamic behavious in bulk and membrane enviroment, and the interface properties of the hIAPP-rIAPP and Aß-hIAPP cross-seeding assemblies. In Chapter I and II, we model and simulate different heteroassemblies formed by the amyloidogenic hIAPP and the nonamyloidogenic rIAPP peptides. The U-shaped hIAPP monomers and oligomers can interact with conformationally similar rIAPP to form stable complexes and to co-assemble into heterogeneous structures via the interfacial hydrogen bonds and hydrophobic contacts at ß-sheet regions. This work demonstrates the existence of cross-interactions between the two different IAPP peptides at the atomic level, providing an improved fundamental understanding of the cross-seeding of different amyloid sequences towards amyloid aggregation and toxicity mechanisms. In Chapter III, IV and V, we investigate the cross-seeding interactions between Aß and hIAPP using a combination of coarse-grained (CG) replica-exchange molecular dynamics (REMD), all-atom molecular dynamics (MD) simulations and Markov Chain Monte Carlo (MCMC) simulations. We for the first time obtain the full free energy landscape for Aß-hIAPP cross-seeding interactions, by which the atomic structure of Aß-hIAPP cross-seeding assembly is determined. Computational mutagenesis studies reveal that disruption of interfacial salt bridges largely disfavor the ß-sheet-to-ß-sheet association, highlighting the importance of salt bridges in the formation of cross-seeding assemblies. We also probe the behaviors of Aß-hIAPP cross-seeding assemblies on zwitterionic POPC and anionic POPC/POPG membranes, determining the specific orientations and demonstrating that electrostatic interactions are the major forces governing peptide-lipid interactions. This work confirms the cross-seeding interactions between Aß and hIAPP, explaining the potential pathological link between AD and T2D. The atomic insights into the cross-seeding intearctions between amyloid peptides obtained from this work are expected to improve the understanding of the amyloid peptides and inspire the peptide inhibitor design towards the neurodegenerative diseases.