pH modulates amyloid- <i>β</i> 42 conformation in lipid membranes: evidence from circular dichroism, Raman spectroscopy, and molecular dynamics simulations

Alzheimer's disease (AD) progression is strongly linked to conformational changes of amyloid-<i>β</i>42 (A<i>β</i>42) in neuronal membranes. This study examined the influence of pH on A<i>β</i>42 conformation in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) membranes using Raman spectroscopy, circular dichroism (CD), and molecular dynamics (MD) simulations. At acidic pH (5.5), A<i>β</i>42 predominantly adopted α-helical structures (∼75-80%), whereas neutral (pH 7.4) and alkaline conditions (pH 9.5) reduced α-helical content to ∼48-58% and ∼44-47%, respectively, with a corresponding rise in random-coil structures (∼20-36%). Across all pH conditions, <i>β</i>-sheet content remained minimal, although MD trajectories indicated transient β-bridge contacts suggestive of early aggregation. MD analyses revealed modest pH-dependent perturbations in bilayer thickness and lipid order. Consistency across experimental and computational methods highlights pH as a critical modulator of A<i>β</i>42 structural dynamics in membranes, providing mechanistic insight into its neurotoxic potential and informing future therapeutic strategies.