Tyrosine Regulates β-Sheet Structure Formation in Amyloid-β₄₂: A New Clustering Algorithm for Disordered Proteins

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• The amyloid-β42 (Aβ42) peptide's single Tyrosine (Tyr) residue is known to be reactive with ligands.
• The precise function of Tyr in Aβ42 structure and aggregation remains unclear.
• Understanding Tyr's role is critical for Aβ42-related research, including Alzheimer's disease.

Purpose of the Study:

• To elucidate the role of the Tyr residue in Aβ42 structure and function.
• To investigate the impact of a Tyr10Ala mutation on Aβ42's structural ensemble.
• To explore novel computational strategies for analyzing protein disorder and stability.

Main Methods:

• Analysis of the Tyr10Ala mutation's effect on Aβ42 structural ensemble.
• Development and application of a new algorithm for predicting stability and order in disorder.
• Utilizing intrinsic disorder predictors and computational aggregation prediction tools.
• Thermodynamic studies employing harmonic and quasi-harmonic methods.

Main Results:

• Tyr residue is vital for beta-sheet formation in Aβ42.
• Tyr10Ala mutation significantly suppresses beta-sheet emergence in monomeric Aβ42.
• The Tyr10Ala mutant exhibits less stable and less compact structures.
• Mutation decreases Aβ42's propensity for disorder and reduces aggregation potential.
• Mid-domain and terminal region interactions are weakened by the Tyr10Ala mutation.

Conclusions:

• Tyr plays a critical role in Aβ42 beta-sheet formation and self-assembly.
• The Tyr10Ala mutation disrupts Aβ42's structural integrity and aggregation behavior.
• The developed "order in disorder" algorithm and stability prediction strategy offer new tools for drug design.
• Targeting Tyr interactions could be a potential therapeutic strategy for Aβ42-related pathologies.