This study reveals the mechanism of arginine (Arginine) in protein aggregation inhibition through experiments and computational simulations. It was found that Arginine can contribute to the formation of biologically inactive emergent complexes by hindering the interaction between negatively charged side chains and proteins. The results of this study provide insight into the mechanisms of protein aggregation and Arginine intervention.
Method
Molecular Dynamics Simulation: Use molecular dynamics simulation to study the interaction between Arginine and proteins.
Fluorescence Spectroscopy: Perform fluorescence spectroscopy to study changes in protein aggregation patterns.
Combined Conformational Dynamics Analysis: Analyse how Arginine guides the evolution of protein structures.
Bioinformatics tools: Use bioinformatics tools to investigate protein structure and aggregation inhibition mechanisms.
Discussion
Arginine hinders negatively charged side chains: Arginine was found to reduce the potential for protein aggregation by interacting with negatively charged side chains.
Promotes formation of biologically inactive complexes: Arginine inhibits protein aggregation by promoting the formation of biologically inactive emergent complexes.
Structural evolution of proteins: Combined with conformational dynamics analysis, Arginine is able to steer the evolution of protein structures, preventing them from evolving towards aggregation.
Results
Structural features of arginine in aqueous solution
Arginine molecules have a marked tendency to self-associate, forming clusters through head-to-tail hydrogen bonding. At relatively high concentrations, these arginine clusters bind with other clusters and monomeric arginine molecules to each other to form larger clusters. And it is found that the hydrogen bonds between arginine molecules are stronger than those between arginine and water, making self-association thermodynamically more favourable.
Interaction of arginine with proteins
Arginine interacts with aromatic and charged side chains of protein surface residues. Specifically, arginine stabilises partially unfolded intermediates by interacting with aromatic and charged residues via cation-π interactions and salt bridge formation, respectively. At the same time, the self-interaction of arginine leads to the formation of clusters that crowd out protein-protein interactions due to their large size.
Conclusions
This study clarifies the specific mechanism by which arginine inhibits protein aggregation. Arginine can interact with aromatic and charged residues of proteins to stabilise part of the unfolded intermediate state, and its self-association forms clusters that can hinder protein-protein interactions and thus inhibit protein aggregation. This finding provides an important theoretical basis for further understanding of protein stability and the prevention and treatment of related diseases.
Ng Y K, Konermann L. Mechanism of Protein Aggregation Inhibition by Arginine: Blockage of Anionic Side Chains Favors Unproductive Encounter Complexes. Journal of the American Chemical Society, 2024, 146(12): 8394-8406.
For research use only. Not intended for any clinical use.
