Work

Unveiling the phenylalanine coaggregation mechanism for a deep understanding of phenylketonuria disease

Year: 2025

Type: article

Abstract: The abnormal accumulation of phenylalanine is a defining feature of phenylketonuria (PKU) and is Linked to the formation of toxic, amyloid-like fibrils. To investigate the molecular mechanisms underlying this aggregation, we performed all-atom molecular dynamics simulations of zwitterionic phenylalanine at physiological temperature. Systems with varying phenylalanine concentrations were simulated over 500 ns to assess aggregation dynamics, structural stability, and non-covalent interactions. Our results show that phenylalanine rapidly self-assembles into fibrillar structures stabilized by hydrogen bonding and π-π stacking. Higher concentrations led to more compact aggregates, as indicated by radial distribution functions and solvent-accessible surface area analyses. We further examined the coaggregation of alanine with phenylalanine fibrils and found that alanine preferentially binds to zwitterionic terminal regions via hydrogen bonds. This interaction may contribute to the enhanced toxicity of phenylalanine aggregates. These findings provide molecular-level insights into phenylalanine aggregation in PKU and support the development of strategies to mitigate its pathological effects.

Source: Scientific Reports

DOI: 10.1038/s41598-025-19843-5

Authors: Haruna L. Barazorda-Ccahuana, Francesc Mas, Sergio Madurga

Institutions: Catholic University of Santa María, Universitat de Barcelona

Language: English

Topic: Metabolism and Genetic Disorders

Subfield: Clinical Biochemistry

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $2,690