Design and study of in silico binding dynamics of certain isoxazole bearing leads against Aβ-42 and BACE-1 loop in protein fibrillation

Aims: Design of isoxazole bearing leads as dual inhibitors against Amyloid β and BACE-1 loop in protein fibrillation Background: Protein fibrillation is one of the key reasons for several diseases namely Alzheimer’s, Parkinson’s, and many others. One of the key strategies of preventing protein fibrillation is destabilizing the protein fibrils themselves or inhibiting the amyloid fibril-forming pathway in the initial stage. Introduction: Attempts have been taken to design newer leads to inhibit protein fibrillation by targeting β-amyloidogenesis pathway in brain. Exploiting interfenestration between Amyloid β -42 protein and BACE-1 (β-site amyloid precursor protein cleaving enzyme) for amyloidogenesis, studies are undertaken to design dual inhibitor against the same. Method: In vitro binding interactions were found using docking, de novo ligand design, MD simulation study Results: Three compounds bearing isoxazole heterocyclic nucleus were designed which could successfully bind to the hydrophobic raft and salt bridge residues Asp 23-Lys-26 of Amyloid β destabilizing the growing fibril. Additionally, one of our candidate compounds exhibited force of interaction with Thr232 at S3 pocket of BACE-1, interacted with key residue Asp228, Tyr71, and Thr72 of the β-hairpin flap and hydrogen bonding with Gly11 at loop 10s. Conclusion: Protein flexibility dynamics of the Aβ-42 protein revealed that there is a considerable conformational change of the same with or without ligand binding. The lower RMSF of the bound region and reprogramming of residual contacts within the Aβ-42 protein suggested successful binding of the ligand with the protein lowering the access for further β-β dimerization.

Regulatory mechanisms of tau protein fibrillation under the conditions of liquid–liquid phase separation

One of the hallmarks of Alzheimer’s disease and several other neurodegenerative disorders is the aggregation of tau protein into fibrillar structures. Building on recent reports that tau readily undergoes liquid–liquid phase separation (LLPS), here we explored the relationship between disease-related mutations, LLPS, and tau fibrillation. Our data demonstrate that, in contrast to previous suggestions, pathogenic mutations within the pseudorepeat region do not affect tau441’s propensity to form liquid droplets. LLPS does, however, greatly accelerate formation of fibrillar aggregates, and this effect is especially dramatic for tau441 variants with disease-related mutations. Most important, this study also reveals a previously unrecognized mechanism by which LLPS can regulate the rate of fibrillation in mixtures containing tau isoforms with different aggregation propensities. This regulation results from unique properties of proteins under LLPS conditions, where total concentration of all tau variants in the condensed phase is constant. Therefore, the presence of increasing proportions of the slowly aggregating tau isoform gradually lowers the concentration of the isoform with high aggregation propensity, reducing the rate of its fibrillation. This regulatory mechanism may be of direct relevance to phenotypic variability of tauopathies, as the ratios of fast and slowly aggregating tau isoforms in brain varies substantially in different diseases.

Effect of the Air-Water Interface on the Conformation of Amyloid Beta

Using MD simulation the conformation of the fibril forming protein amyloid beta at the air-water interface. It is found that adsorption at the air-water interface induces the formation of aggregation prone alpha-helical conformations, consistent with experimental studies of amyloid beta. Adsorption on the air-water interface also reduces the number of distinct conformations that the protein exhibits. This provides insight into the role of protein conformational change into the enhancement of protein fibrillation at interfaces.

Effect of the Air-Water Interface on the Conformation of Amyloid Beta

Using MD simulation the conformation of the fibril forming protein amyloid beta at the air-water interface. It is found that adsorption at the air-water interface induces the formation of aggregation prone alpha-helical conformations, consistent with experimental studies of amyloid beta. Adsorption on the air-water interface also reduces the number of distinct conformations that the protein exhibits. This provides insight into the role of protein conformational change into the enhancement of protein fibrillation at interfaces.

Effect of the Air-Water Interface on the Conformation of Amyloid Beta

Using MD simulation the conformation of the fibril forming protein amyloid beta at the air-water interface. It is found that adsorption at the air-water interface induces the formation of aggregation prone alpha-helical conformations, consistent with experimental studies of amyloid beta. Adsorption on the air-water interface also reduces the number of distinct conformations that the protein exhibits. This provides insight into the role of protein conformational change into the enhancement of protein fibrillation at interfaces.