Orientation of tyrosine side chain in neurotoxic Aβ differs in two different secondary structures of the peptide

Abstract

Amyloid β (Aβ) peptide is present as a major component in amyloid plaque that is one of the hallmarks of Alzheimer's disease. The peptide contains a single tyrosine residue and Aβ has a major implication in the pathology of the disease progression. Current investigation revealed that the tyrosine side chain attained two different critical stereo orientations in two dissimilar conformational states of the peptide. The extended α-helical structure of the peptide observed in an apolar solvent or methanol/water mixture became disordered in aqueous medium and the radius of gyration decreased. In aqueous medium, the torsional angle around Cα–Cβ of tyrosine group became −60°. However, in its α-helical conformation in an apolar system, the measured angle was 180° and this rotameric state may be reasoned behind stronger tyrosine fluorescence compared with the disordered state of the peptide. Molecular dynamics simulation analyses and spectroscopic studies have helped us to understand the major structural changes in the secondary structure of the peptide in the two conformational states. A conformational clustering indicated that the compact state is more stable with tyrosine residue attaining the torsion angle value of −60°, whereas the native state (in HFIP/water mixture) is prevalent at a torsion angle value of −180°. High solvent accessibility has possibly stabilized the particular rotameric state (−60°) of the tyrosine residue and could be the reason behind decrease in fluorescence of the sole tyrosine residue in an aqueous buffer solution (pH 7.4) compared with its fluorescence in the α-helical structure in the micellar environment.

Interactions of the Aβ(1–42) Peptide with Boron Nitride Nanoparticles of Varying Curvature in an Aqueous Medium: Different Pathways to Inhibit β-Sheet Formation

“…It is found that aromatic residues of the peptide such as Phe4 and Tyr10 drive the trajectories of these systems to different conformations depending on their initial stacking interactions with the BNNT surface. The importance of the tyrosine residue in amyloid formation was also reported in other studies. − The calculated free-energy landscapes reveal a single deep minimum at small R g value for the solvated Aβ(1–42) without any nanoparticles, a wide basin at large R g value for the Aβ(1–42) peptide with BNNS, and a rather complex surface with more localized states for the peptide in the presence of (12,12) BNNT.…”

“…Tyr10 is the only tyrosine residue in the Aβ(1–42) sequence, and it plays a critical role in β-sheet exposure. The importance of Tyr10 was also reported in some of the earlier studies. − …”

Analysis of oligomeric complexes of the amyloid-forming FYLLYY peptide by collision-induced dissociation with electrospray ionization mass spectrometry

“…15,16 The p-p interaction energies and tyrosine (Y)-mediated two-dimensional peptide assembly morphology were reported via quantum calculation or two-dimensional imaging method. [17][18][19][20] The single Y-containing active sequences (LYQLEN from the human insulin chain A, 21 NNQQNY from the yeast prion protein Sup35, [22][23] and VQIVYK from the tau protein [24][25][26] ), known to form ordered oligomers with b-strand structures that mature into fibril structures, have been investigated to better understand the p-p stacking interaction. The collision-induced dissociation (CID)-MS/MS was used to study the oligomer structures of the LYQLEN, NNQQNY, and VQIVYK sequences.…”

Rotamer Dynamics: Analysis of Rotamers in Molecular Dynamics Simulations of Proteins

“…Previous studies employing MD analysis and focusing on rotamers often represented their data via plotting changes in c dihedral angles over time (7,8) or through principal component analysis (9). Although few dihedral angles are easy to plot, a simple classification scheme is required when dealing with large number of heterogeneous residues.…”