Identification of new pentapeptides as potential inhibitors of amyloid-beta(42) aggregation using virtual screening and molecular dynamics simulations

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly characterized by extracellular accumulation of amyloid- ss (A ss) peptide. Previous studies reported pentapeptide RIIGL as an effective inhibitor of A ss aggregation and neurotoxicity induced by A ss aggregates. In this work, a library of 912 pentapeptides based on RIIGL has been designed and assessed for their efficacy to inhibit A ss(42) aggregation using computational techniques. The top hit pentapeptides revealed by molecular docking were further assessed for their binding affinity with A ss 42 monomer using MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) method. The MM-PBSA analysis identified RLAPV, RVVPI, and RIAPA, which bind to A ss 42 monomer with a higher binding affinity -55.80, -46.32, and -44.26 kcal/mol, respectively, as compared to RIIGL (Delta G(binding) = 41.29 kcal/mol). The residue-wise binding free energy predicted hydrophobic contacts between A ss 42 monomer and pentapeptides. The secondary structure analysis of the conformational ensembles generated by molecular dynamics (MD) depicted remarkably enhanced sampling of helical and no ss-sheet conformations in A ss 42 monomer on the incorporation of RVVPI and RIAPA. Notably, RVVPI and RIAPA destabilized the D23-K28 salt bridge in A ss 42 monomer, which plays a crucial role in A ss 42 oligomer stability and fibril formation. The MD simulations highlighted that the incorporation of proline and arginine in pentapeptides contributed to their strong binding with A ss 42 monomer. Furthermore, RVVPI and RIAPA prevented conformational conversion of A ss 42 monomer to aggregation-prone structures, which, in turn, resulted in a lower aggregation tendency of A ss 42 monomer.

Automated summary

Alzheimer's disease is a neurodegenerative disease characterized by accumulation of amyloid-beta (Aβ) peptide. This study designed and evaluated a library of 912 pentapeptides based on RIIGL for their potential to inhibit Aβ(42) aggregation using computational techniques. The pentapeptides RLAPV, RVVPI, and RIAPA showed higher binding affinity to Aβ(42) monomer compared to RIIGL, and they also prevented conformational conversion and destabilized crucial salt bridge in Aβ(42) monomer, leading to lower aggregation tendency.