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Keywords:

  • Alzheimer's disease;
  • amyloid;
  • protein aggregation rate;
  • prion protein;
  • species barrier;
  • genetic algorithm;
  • molecular dynamics

Abstract

The reliable identification of β-aggregating stretches in protein sequences is essential for the development of therapeutic agents for Alzheimer's and Parkinson's diseases, as well as other pathological conditions associated with protein deposition. Here, a model based on physicochemical properties and computational design of β-aggregating peptide sequences is shown to be able to predict the aggregation rate over a large set of natural polypeptide sequences. Furthermore, the model identifies aggregation-prone fragments within proteins and predicts the parallel or anti-parallel β-sheet organization in fibrils. The model recognizes different β-aggregating segments in mammalian and nonmammalian prion proteins, providing insights into the species barrier for the transmission of the prion disease.