Computational design and evaluation of β-sheet breaker peptides for destabilizing Alzheimer's amyloid-β42 protofibrils

The beta-sheet breaker (BSB) peptides interfere with amyloid fibril assembly and used as therapeutic agents in the treatment of Alzheimer's disease (AD). In this regard, a simple yet effective in silico screening methodology was applied in the present study to evaluate a potential 867 pentapeptide library based on known BSB peptide, LPFFD, for destabilizing A beta(42) protofibrils. The molecular docking based virtual screening was used to filter out pentapeptides having binding affinities stronger than LPFFD. In the next step, binding free energies of the top 10 pentapeptides were evaluated using the MM-PBSA method. The residue-wise binding free energy analysis reveals that two pentapeptides, PVFFE, and PPFYE, bind to the surface of A beta(42) protofibril and another pentapeptide, PPFFE, bind in the core region of A beta(42) protofibril. By employing molecular dynamics simulation as a post filter for the top-hit peptides from MM-PBSA, the pentapeptides, PPFFE, PVFFE, and PPFYE, have been identified as potential BSB peptides for destabilizing A beta(42) protofibril structure. The conformational microstate analysis, a significant decrease in the beta-sheet content of A beta(42) protofibril, a loss in the total number of hydrogen bonds in A beta(42) protofibril, Asp23-Lys28 salt bridge destabilization and analysis of the free energy surfaces highlight A beta(42) protofibril structure destabilization in presence of pentapeptides. Among three top-hit pentapeptides, PPFFE displayed the most potent A beta(42) protofibril destabilization effect that shifted the energy minima toward lowest value of beta-sheet content as well as lowest number of hydrogen bonds in A beta(42) protofibril. The in silico screening workflow presented in the study highlight an alternative tool for designing novel peptides with enhanced BSB ability as potential therapeutic agents for AD.