A Molecular Dynamics Investigation into Optimum Membrane‐Cholesterol Performance Influencing Alzheimer's‐Related Amyloid‐β Conformational Stability

Abstract Alzheimer's disease (AD) is associated with the aggregation of amyloid beta (Aβ) peptides, which disrupt membrane integrity and contribute to neurodegeneration. Cholesterol, a key membrane component, plays a role in modulating these pathological events by stabilizing membrane structure and affecting protein dynamics. This study investigates how cholesterol influences membrane stability in the presence of Aβ1‐42, a peptide linked to AD progression. Molecular dynamics (MD) simulations are used to model a dipalmitoylphosphatidylcholine (DPPC) lipid bilayer with cholesterol concentrations ranging from 10–50%. Aβ1‐42 is modeled to examine its interaction with these cholesterol‐rich membranes. Key parameters, including root mean square deviation (RMSD) for structural stability, root mean square fluctuation (RMSF) for local flexibility, and hydrogen bonding (H‐bonding) are calculated to assess interactions between Aβ1‐42 and the lipid bilayer. Secondary structure analysis (SSA) tracked conformational changes in Aβ1‐42, focusing on transitions between alpha helices and beta sheets, which are critical for understanding peptide misfolding. Results of this study indicate that approximately (≈) 30% cholesterol concentration is optimal for enhancing peptide stability. While higher cholesterol (50%) further stabilizes the membrane, it leads to diminishing returns on peptide stability, possibly due to excessive membrane rigidity. These findings suggest that a balance between membrane rigidity and peptide flexibility is crucial for maintaining structural stability in AD.