Effects of Bare and PEG Coated Gold Nanoparticles on RRM2 Protein: A Pathway Analysis and MD Simulations Approach

Nanoscience Chemistry Materials Science Bioengineering Biophysics Biochemistry Life Sciences
gold nanoparticles metabolic pathway analysis protein-protein interaction network molecular dynamics simulations RRM2 protein PEG coating biocompatibility

Academic Background

Nanoparticles (NPs) have increasingly been applied in the medical field, particularly in bioimaging, biosensing, and drug delivery. Gold nanoparticles (AuNPs), due to their unique physicochemical properties, have become a focal point in biomedical research. However, despite their significant therapeutic potential, the biosafety of AuNPs remains controversial. Once nanoparticles enter biological systems, they may interact with biomolecules such as proteins and DNA, potentially altering their structure and function. Therefore, investigating the interaction mechanisms between nanoparticles and proteins is crucial for developing safer and more efficient nanodrug delivery systems.

This study aims to explore the effects of bare gold nanoparticles and polyethylene glycol (PEG)-coated gold nanoparticles on the RRM2 protein through metabolic pathway analysis and molecular dynamics (MD) simulations. The RRM2 protein is a key enzyme in the glutathione metabolic pathway, closely related to DNA synthesis. By studying the interaction between AuNPs and the RRM2 protein, the impact of nanoparticles on protein structure and function can be elucidated, providing a theoretical basis for the design and optimization of nanodrugs.

Source of the Paper

This paper was co-authored by Ajit Kumar Singh and Anupam Nath Jha from the Department of Molecular Biology and Biotechnology at Tezpur University, India, and published in the 2025 issue of Bionanoscience (DOI: 10.1007/s12668-025-01922-6). The research was funded by the Department of Science and Technology, India.

Research Process

1. Metabolic Pathway and Protein-Protein Interaction Network Analysis

The study first retrieved the human glutathione metabolic pathway (hsa00480) from the KEGG database and constructed a protein-protein interaction (PPI) network. Using Cytoscape software, the network was analyzed to identify the key protein RRM2. RRM2 plays a critical role in the glutathione metabolic pathway and is closely associated with various diseases, such as cancer and leukemia.

2. System Construction

The study used the Nanomaterial Modeler module of CHARMMM-GUI to construct models of bare gold nanoparticles and PEG-coated gold nanoparticles with a diameter of 5 nm. The structure of the RRM2 protein was obtained from the UniProt database, and the structure with PDB ID 3OLJ was selected for simulation. Six different systems were designed, including RRM2 protein alone, four complexes of RRM2 with bare gold nanoparticles in different orientations, and a complex of RRM2 with PEG-coated gold nanoparticles.

3. Molecular Dynamics Simulation

The study employed GROMACS 2020.4 software for molecular dynamics simulations, with a simulation time of 100 ns. The systems underwent energy minimization, NVT, and NPT equilibration before production simulations. The simulation trajectories were analyzed using parameters such as RMSD (root mean square deviation), RMSF (root mean square fluctuation), and RG (radius of gyration) to assess the structural stability of the protein.

4. Secondary Structure Analysis

Using the DSSP (Define Secondary Structure of Proteins) tool, the study analyzed changes in the secondary structure of the RRM2 protein during the simulation. The results showed that PEG-coated gold nanoparticles had a minimal impact on the protein’s secondary structure, indicating that PEG coating enhances the biocompatibility of nanoparticles.

5. Interaction Analysis

The study analyzed the interactions between the RRM2 protein and gold nanoparticles by calculating non-bonded interactions and contact surface area (CSA). The results demonstrated that PEG-coated gold nanoparticles had fewer interactions with the protein, further confirming the “stealth” effect of PEG coating.

6. Free Energy Landscape Analysis

Through free energy landscape (FEL) analysis, the study evaluated the energy stability of the RRM2 protein in different systems. The results showed that the complex of PEG-coated gold nanoparticles and the protein had lower energy, indicating greater structural stability.

Main Results

  1. Metabolic Pathway Analysis: RRM2 protein was identified as a key node in the glutathione metabolic pathway, closely related to DNA synthesis.
  2. Molecular Dynamics Simulation: Bare gold nanoparticles had a certain impact on the structure of the RRM2 protein, while PEG-coated gold nanoparticles had a minimal effect.
  3. Secondary Structure Analysis: PEG-coated gold nanoparticles significantly reduced changes in the protein’s secondary structure, indicating higher biocompatibility.
  4. Interaction Analysis: PEG-coated gold nanoparticles had fewer interactions with the protein, suggesting that PEG coating can modulate the surface properties of nanoparticles.
  5. Free Energy Landscape Analysis: The complex of PEG-coated gold nanoparticles and the protein had lower energy, indicating greater structural stability.

Conclusion and Significance

This study, through metabolic pathway analysis and molecular dynamics simulations, revealed the effects of bare gold nanoparticles and PEG-coated gold nanoparticles on the RRM2 protein. The results demonstrated that PEG-coated gold nanoparticles exhibit higher biocompatibility and cause minimal structural changes to the protein, providing an important theoretical basis for the design and optimization of nanodrugs. This research not only deepens the understanding of the interaction mechanisms between nanoparticles and proteins but also offers new insights for developing safer and more efficient nanodrug delivery systems.

Research Highlights

  1. Innovative Methodology: The study combined metabolic pathway analysis and molecular dynamics simulations, providing a new methodological framework for studying nanoparticle-protein interactions.
  2. Key Findings: PEG-coated gold nanoparticles had a minimal impact on protein structure, indicating higher biocompatibility.
  3. Application Value: The research results provide a significant theoretical basis for the design and optimization of nanodrugs, contributing to the development of safer and more efficient nanodrug delivery systems.

Other Valuable Information

The study also found that PEG-coated gold nanoparticles had fewer interactions with the protein, suggesting that PEG coating can modulate the surface properties of nanoparticles and reduce non-specific interactions with biomolecules. This discovery offers new ideas for the surface modification of nanoparticles, aiding in the enhancement of the targeting and biocompatibility of nanodrugs.