Conformational Features of Aβ25-35 and Its Mutants Suggest Toxic Structural Determinants: Insights from REST2 Simulations.

Abstract

The Aβ25-35 fragment is the shortest proteolytic fragment retaining the core neurotoxicity of full-length Alzheimer's amyloid-β (Aβ). To elucidate the structure-neurotoxicity relationships, we performed replica exchange with solute tempering 2 (REST2) simulations on wild-type (WT), N27A (less toxic), and M35A (more toxic) Aβ25-35 hexamers in explicit solvent. Our simulations show that N27A, WT, and M35A hexamers predominantly adopt 4-stranded, 6-stranded, and 5-stranded β-barrels, respectively, driven by hydrophobic interactions within residues I30-G33. Hydrogen bond counts and binding energies for adjacent peptide contacts and peptide-water interactions indicate that both β-barrel disassembly propensity and N-terminal hydration (residues G25-K28) correlate with the cytotoxicity trend (N27A < WT < M35A). Integrating our findings with established membrane damage mechanisms, we propose that (I) the disassembly propensity of dominant β-barrels governs their transition from off-pathway states to cytotoxic oligomers, and (II) N-terminal domain exposure (G25-K28) in on-pathway intermediates modulates peptide-membrane interactions. To reduce Aβ25-35 oligomeric toxicity, we recommend inhibiting hydrophobic core residues (A30-G33) to suppress aggregation and modulating N-terminal contacts to limit solvent exposure and membrane binding. Our simulations provide new insights into WT and mutant Aβ25-35 cytotoxicity and suggest therapeutic strategies for its attenuation.