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.