Screening Aggregation Breakers of Alzheimer’s Disease Aβ Protofibrils Using AutoDock CrankPep

Alzheimer’s disease (AD) is a neurodegenerative disorder putatively caused by the accumulation of β-amyloid (Aβ) peptides in the brain. To treat AD, drugs and small peptides that inhibit Aβ peptide aggregation are being explored as potential therapies. With the goal of elucidating the molecular interactions between Aβ peptides and potential inhibitors to explore their therapeutic effect, we used AutoDock CrankPep (ADCP) to simulate the docking of small peptide inhibitors that act as aggregation breakers preventing incoming Aβ peptides from adsorbing to protofibrils. We considered the known aggregation breakers KLVFF, GSGFK, and LPFFD. The Aβ protofibril was derived from PDB ID 2LMO extracting residues 16-35 from chains A-F to produce a U-shaped fibril. The choice of this protofibril was partially due to the requirements of ADCP, which only accepts peptides that are 20 amino acids or less in length. We assessed the impact of aggregation breakers on incoming Aβ peptide binding by running ADCP simulations with and without aggregation breaker peptide inhibitors present. Our approach therefore permits us to measure the change in energetics and molecular contacts of incoming Aβ peptides with the protofibril due to inhibitors. We demonstrate that ADCP is a useful tool to screen aggregation breakers and estimate their potential therapeutic benefit.