Effects of Solvent on the Structure of the Alzheimer Amyloid-β(25–35) Peptide

The free energy landscape for folding of the Alzheimer’s amyloid-β(25–35) peptide is explored using replica exchange molecular dynamics in both pure water and in HFIP/water cosolvent. This amphiphilic peptide is a natural by-product of the Alzheimer’s amyloid-β(1–40) peptide and retains the toxicity of its full-length counterpart as well as the ability to aggregate into β-sheet-rich fibrils. Our simulations reveal that the peptide preferentially populates a helical structure in apolar organic solvent, while in pure water, the peptide adopts collapsed coil conformations and to a lesser extent β-hairpin conformations. The β-hairpin is characterized by a type II′β-turn involving residues G29 and A30 and two short β-strands involving residues N27, K28, I31, and I32. The hairpin is stabilized by backbone hydrogen-bonding interactions between residues K28 and I31; S26 and G33; and by side-chain-to-side-chain interactions between N27 and I32. Implications regarding the mechanism of aggregation of this peptide into fibrils and the role of the environment in modulating secondary structure are discussed.