Tyrosine Regulates β-sheet Structure Formation in Amyloid-β42: A New Clustering Algorithm for Disordered Proteins
Document Type
Article
Publication Date
2017
Keywords
Chemical Structure, Diseases and Disorders, Genetics, Nucleic Acid Structure, Peptides and Proteins
Digital Object Identifier (DOI)
https://doi.org/10.1021/acs.jcim.6b00761
Abstract
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.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Journal of Chemical Information Modeling, v. 57, issue 6, p. 1342-1358
Scholar Commons Citation
Coskuner, Orkid and Uversky, Vladimir N., "Tyrosine Regulates β-sheet Structure Formation in Amyloid-β42: A New Clustering Algorithm for Disordered Proteins" (2017). Molecular Medicine Faculty Publications. 860.
https://digitalcommons.usf.edu/mme_facpub/860
