Arginine and disordered amyloid-β peptide structures: molecular level insights into the toxicity in Alzheimer's disease.

Recent studies present that the single arginine (R) residue in the sequence of Aβ42 adopts abundant β-sheet structure and forms stable salt bridges with various residues. Furthermore, experiments proposed that R stimulates the Aβ assembly and arginine (R) to alanine (A) mutation (R5A) decreases both aggregate formation tendency and the degree of its toxicity. However, the exact roles of R and R5A mutation in the structures of Aβ42 are poorly understood. Extensive molecular dynamics simulations along with thermodynamic calculations present that R5A mutation impacts the structures and free energy landscapes of the aqueous Aβ42 peptide. The β-sheet structure almost disappears in the Ala21-Ala30 region but is more abundant in parts of the central hydrophobic core and C-terminal regions of Aβ42 upon R5A mutation. More abundant α-helix is adopted in parts of the N-terminal and mid-domain regions and less prominent α-helix formation occurs in the central hydrophobic core region of Aβ42 upon R5A mutation. Interestingly, intramolecular interactions between N- and C-terminal or mid-domain regions disappear upon R5A mutation. The structures of Aβ42 are thermodynamically less stable and retain reduced compactness upon R5A mutation. R5A mutant-type structure stability increases with more prominent central hydrophobic core and mid-domain or C-terminal region interactions. Based on our results reported in this work, small organic molecules and antibodies that avoid β-sheet formation in the Ala21-Ala30 region and hinder the intramolecular interactions occurring between the N-terminal and mid-domain or C-terminal regions of Aβ42 may help to reduce Aβ42 toxicity in Alzheimer's disease.