Computational insights into terpene-induced modulation of amyloid-β peptide (Aβ1–42) aggregation-favoring conformations

Abstract

Alzheimer's disease (AD) is characterized by progressive neurodegeneration, with aggregation of amyloid-β (Aβ_1–42) playing a central role. Natural terpenes have emerged as promising therapeutic candidates due to their bioactivity. Here, we investigated caryophyllene and copaene interactions with Aβ_1–42 via molecular docking, molecular dynamics simulations, and MM/PBSA calculations. Both terpenes bound effectively to distinct Aβ_1–42 pockets, altering structural flexibility and disrupting aggregation-prone regions, mainly within the C-terminal and central hydrophobic domains. Inter-residue distance matrices showed increased separation between peptide segments, reducing compactness and potentially hindering β-sheet nucleation. Secondary structure analysis revealed decreased β-sheet content and preservation of α-helices, especially for caryophyllene in pocket 1 and copaene in pocket 2. Binding free energy analysis confirmed favorable thermodynamics dominated by hydrophobic interactions. These findings suggest caryophyllene and copaene interfere with early Aβ_1-42 aggregation steps, supporting their potential as natural scaffolds for anti-amyloid drug development in AD.