Polyproline chains destabilize the Alzheimer's amyloid-β protofibrils: A molecular dynamics simulation study

Alzheimer's is a fatal neurodegenerative disease for which there is no cure at present. The disease is characterized by the presence of plaques, principally comprising the amyloid-beta peptide (viz., beta-sheet) in the brains of a patient. In our present work, we study the interaction of these beta-sheets with a different number of repeating units of proline (beta-sheet breaker) by docking and all atom molecular dynamics simulations. Our results indicate that proline can break the amyloid protofibrils apart, cause them to break their beta-sheet structure, and in some cases even induce the formation of 3(10) helices, which may be intermediates in the unfolding of these beta-sheets. We have also observed that some of the important hydrogen bonds and salt bridges between chains were disrupted by proline and the tight interatomic packing of atoms in the fibrils was made relatively loose. Proline chains had a tendency to make several contacts with charged residues. Proline chains binded well to the fibrils by strong electrostatic interactions while hydrophobic interactions played a less important role. This leads to the conclusion that proline can break the amyloid fibrils apart and can be considered in the design of novel peptide-based drugs to treat Alzheimer's disease and potentially other diseases caused by the misfolding of proteins into beta-sheets. (C) 2019 Elsevier Inc. All rights reserved.