Influence of polar amino acids in the evolution of the phenylalanine and phenylalanine dipeptide self-assembly: towards the study of diverse morphologies

Abstract

Self-assembly is a natural process where disordered molecules organize into structured formations, playing a crucial role in the development of amyloid fibrils associated with degenerative diseases such as Alzheimer’s, Parkinson’s, and type 2 diabetes. L-phenylalanine (Phe), an essential aromatic amino acid required for protein synthesis, also serves as a precursor for important biomolecules like tyrosine and dopamine. Under certain physiological conditions, excess Phe can aggregate into amyloid fibrils, which contribute to neurotoxic effects observed in metabolic disorders such as phenylketonuria (PKU). However, diphenylalanine (Phe-Phe) peptides, which serve as core recognition motifs of amyloid plaques associated with neurological disorders like Alzheimer’s and Parkinson’s, are also of particular interest. The formation of these fibrils is driven by interactions like hydrogen bonding, π-π stacking, and van der Waals’ forces, leading to structures with hydrophobic surfaces and charged cores that disrupt cellular functions and contribute to toxicity. This research explores the influence of polar amino acids on the self-assembly of L-Phe and Phe-Phe. The results show that polar amino acids, including L-arginine, L-lysine, and L-glutamic acid, effectively inhibit the formation of Phe fibrillar structures. Specifically, L-arginine and L-lysine demonstrate strong capability to prevent fibril development in Phe-Phe systems. Observations were validated using optical microscopy, Confocal laser scanning microscopy, Scanning electron microscopy, UV-visible spectroscopy, and Zeta potential. These findings suggest that polar amino acids can modulate amyloid aggregation, providing valuable insights into potential strategies for managing diseases related to amyloid fibril formation.