Curiosity-driven de novo protein design via polymerized amyloids

Abstract

Repeat proteins, known for their modularity, are focal points of de novo protein design. This study adopts a curiosity-driven approach to explore and discover proteins with repeated sequences. Leveraging AlphaFold 2, we initially bias our sequence design by integrating amyloid β42 with a random hexapeptide linker, achieving high foldability in over 12% of cases through polymerization. Without targeting a structural specification, we evolve these structures into a mosaic of folds using segmental mutations and genetic algorithms. The majority of these de novo structures demonstrate good stability in silico through molecular dynamics simulation. Additionally, we investigate the compatibility of medial strands to assess potential variations in structural integrity upon mutation. This curiosity-driven approach not only underscores the evolvability and versatility of repeat proteins but also highlights the potential for developing peptide-based pharmaceuticals and functional materials.