Destabilization of the Alzheimer's amyloid-β peptide by a proline-rich β-sheet breaker peptide: a molecular dynamics simulation study.

The amyloid-β peptide exists in the form of fibrils in the plaques found in the brains of patients with Alzheimer's disease. One of the therapeutic strategies is the design of molecules which can destabilize these fibrils. We present a designed peptide KLVFFP5 with two segments: the self-recognition sequence KLVFF and a β-sheet breaker proline pentamer. Molecular dynamics simulations and docking results showed that this peptide could bind to the protofibrils and destabilize them by establishing hydrophobic contacts and hydrogen bonds with a higher affinity than the KLVFF peptide. In the presence of the KLVFFP5 peptide, the β-sheet content of the protofibrils was reduced significantly; the hydrogen bonding network and the salt bridges were disrupted to a greater extent than the KLVFF peptide. Our results indicate that the KLVFFP5 peptide is an effective β-sheet disruptor which can be considered in the therapy of Alzheimer's disease.