Our recent studies show that the single Tyr residue in the sequence of amyloid-β₄₂ (Aβ₄₂) is reactive toward various ligands, including metals and adenosine trisphospate (see: Coskuner , O. J. Biol. Inorg. Chem. 2016 , 21 , 957 - 973 and Coskuner , O. ; Murray , I. V. J. J. Alzheimer's Dis. 2014 , 41 , 561 - 574 ). However, the exact role of Tyr in the structures of Aβ₄₂ remains unknown. To fill this gap, here we analyzed the role of Tyr and the impact of the Tyr10Ala mutation on the structural ensemble of Aβ₄₂. β-Sheet formation in the structural ensemble of Aβ₄₂ is directly associated with the reactivity of this peptide toward ligand-receptor interactions, including self-assembly. On the basis of our findings, Tyr plays a crucial role in β-sheet emergence in the structures of Aβ₄₂, and the Tyr10Ala mutation greatly suppresses or diminishes β-sheet formation in the overall structures of monomeric Aβ₄₂. A new strategy for predicting the degree of stability and an "order in disorder" algorithm using secondary structure properties and thermodynamics were developed and applied for the Tyr10Ala mutant and wild-type Aβ₄₂ analysis. This new clustering algorithm may help in selecting disordered protein structure ensembles for drug design studies. Tyr10Ala mutation results in less stable and less compact structures, a conclusion based on our varying thermodynamic studies using harmonic and quasi-harmonic methods. Furthermore, the use of various intrinsic disorder predictors suggests that the Tyr10Ala mutation impacts the Aβ₄₂ propensity for disorder, whereas the application of several computational tools for aggregation prediction suggests that this mutation decreases the Aβ₄₂ aggregation propensity. The mid-domain interactions with the N- and C-terminal regions weaken or disappear upon Tyr10Ala mutation. In addition, the N- and C-terminal interactions are weaker or diminished upon the introduction of the Tyr10Ala mutation to the structures of the Aβ₄₂ peptide in solution.