In Silico Studies to Predict the Role of Solvent in Guiding the Conformations of Intrinsically Disordered Peptides and Their Aggregated Protofilaments

Abstract

The formation of amyloids due to the self-assembly of intrinsically disordered proteins or peptides is a hallmark for different neurodegenerative diseases. For example, amyloids formed by the amyloid beta (Aβ) peptides are responsible for the most devastating neuropathological disease, namely, Alzheimer’s disease, while aggregation of α-synuclein peptides causes the etiology of another neuropathological disease, Parkinson’s disease. Characterization of the intermediates and the final amyloid formed during the aggregation process is, therefore, crucial for microscopic understanding of the origin behind such diseases, as well as for the development of proper therapeutics to combat those. However, most of the research activities reported in this area have been directed toward examining the early stages of the aggregation process, including probing the conformational characteristics of the responsible protein/peptide in the monomeric state or in small oligomeric forms. This is because the small soluble oligomers have been found to be more deleterious than the final insoluble amyloids. This review discusses some of the recent findings obtained from our simulation studies on Aβ and α-synuclein monomers and small preformed Aβ aggregates. A molecular-level insight of the aggregation process with a special emphasis on the role of water in inducing the aggregation process has been provided.

Protein Painting Mass Spectrometry in the Discovery of Interaction Sites within the Acetylcholine Binding Protein

“…44 Various methods have been used to address this problem including biocomputational modeling of Aβ structures based on evolutionary sequence alignment algorithms. 45 Interactions between Aβ42 and nAChRs are well reported in the literature, and functional evidence suggests competitive interactions between Aβ42 and α7 as well as α7β2 nAChR ligands. 46 Our results show that Aβ42 exhibits some similarity to Bgtx in the protein binding sites within the Ac-AChBP.…”

“…However, it is not yet clear how amyloid peptide properties including self-assembly (monomeric vs oligomeric) participate in this disease . Various methods have been used to address this problem including biocomputational modeling of Aβ structures based on evolutionary sequence alignment algorithms . Interactions between Aβ42 and nAChRs are well reported in the literature, and functional evidence suggests competitive interactions between Aβ42 and α7 as well as α7β2 nAChR ligands .…”