Computational disruption of paired helical filaments (PHFs) assembly using Milk Lactalbumin-derived peptides against Alzheimer's disease

Peptides show great potential in diagnosing and treating Alzheimer's disease (AD), particularly by targeting amyloid-beta plaques and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau proteins. This study focuses on designing peptide inhibitors from bovine milk alpha-lactalbumin to reduce tau aggregation in AD. Using computational techniques, such as docking, molecular dynamics simulations, and mutagenesis, we evaluated the binding and stability of these peptides against the paired helical filament (PHF) core. Our results identified promising inhibitors, with p136 emerging as the most effective. It significantly altered the PHF core's structure, preventing further aggregation by blocking additional subunits. Additionally, p76 displayed strong binding against straight filaments (SFs). These findings highlight the potential of peptides derived from bovine milk alpha-lactalbumin as diagnostic and therapeutic tools for AD, with p136 standing out as a promising candidate for disrupting tau aggregation. • Bovine milk alpha-lactalbumin was used as a template to design peptides to inhibit the PHFs, a hallmark of AD.Computational methods were employed to evaluate the interactions and binding efficacy of the peptides with PHF cores. • Among the peptides tested, p67, p76, and p136 showed significant binding to the PHF core. • MD simulations revealed that p67 and p76 caused minimal conformational changes to the PHF core, while p136 led to notable structural disruptions. • The peptides p67, p76, and p136 were shown to prevent the binding of additional PHF subunits, thereby inhibiting further aggregation. • Peptide p76 exhibited the most potent binding ability against straight filaments (SFs) among the peptides tested.