Tyrosine regulates beta-sheet structure formation in amyloid-beta(42): a new clustering algorithm for disordered proteins

Abstract

Our recent studies show that the single Tyr residue in the sequence of amyloid-beta(42) (A beta(42)) 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 A(beta 42) remains unknown. To fill this gap, here we analyzed the role of Tyr and the impact of the TyrlOAla mutation on the structural ensemble of A beta(42). beta-Sheet formation in the structural ensemble of A beta(42) 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 beta-sheet emergence in the structures of A beta(42), and the TyrlOAla mutation greatly suppresses or diminishes beta-sheet formation in the overall structures of monomeric A beta(42). 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 A beta(42) analysis. This new clustering algorithm may help in selecting disordered protein structure ensembles for drug design studies. TyrlOAla 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 TyrlOAla mutation impacts the A beta(42) propensity for disorder, whereas the application of several computational tools for aggregation prediction suggests that this mutation decreases the A beta(42) aggregation propensity. The mid-domain interactions with the N- and C-terminal regions weaken or disappear upon TyrlOAla mutation. In addition, the N- and C-terminal interactions are weaker or diminished upon the introduction of the TyrlOAla mutation to the structures of the A beta(42) peptide in solution.