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Fate of amine-based selenenyl sulfides during interaction with glutathione reductase: a molecular dynamics perspective

Vishnu Rama Chari, Raghu Nath Behera

TL;DR

The paper addresses the lack of force-field parameters for Se–S-containing ligands and investigates how amine-based selenenyl sulfides interact with the catalytic site of glutathione reductase (GR). It develops GAFF-compatible parameters for Se–S bonds using a phenyl selenide backbone and validates them through 200 ns MD simulations of RSeSG–GR complexes, following geometry optimization, docking, and RESP charge fitting. The results show that the presence and nature of the amino group and its substituent crucially influence the ligand’s ability to approach the GR active site, with compound 2b achieving a favorable orientation toward SCys-58 while 1b fails and 3b is hindered by a bulky substituent. Overall, MD reveals dynamic, orientation-dependent interactions that complement prior docking studies and indicate a real possibility for RSeSG reduction at GR, informing design strategies for enhanced GPx-mimic activity.

Abstract

In the search for small organoselenium-based mimics of the glutathione peroxidase (GPx) enzyme, it has been observed that selenenyl sulfides (RSeSG) derived from amine-based GPx mimics have the potential to be reduced at the catalytic site of glutathione reductase (GR), thereby enhancing the catalytic efficiency of these mimics in biological systems. However, molecular insights into these interactions are lacking due to the absence of force field parameters for Se-S containing compounds. In this study, we present force field parameters for selenenyl sulfides with a phenyl selenide backbone developed using the General Amber Force Field (GAFF). Employing these parameters, a 200 ns molecular dynamics (MD) simulation of RSeSG was performed. The results indicate that both the amino nitrogen and its substituent significantly influence the interaction of RSeSG at the catalytic site of GR.

Fate of amine-based selenenyl sulfides during interaction with glutathione reductase: a molecular dynamics perspective

TL;DR

The paper addresses the lack of force-field parameters for Se–S-containing ligands and investigates how amine-based selenenyl sulfides interact with the catalytic site of glutathione reductase (GR). It develops GAFF-compatible parameters for Se–S bonds using a phenyl selenide backbone and validates them through 200 ns MD simulations of RSeSG–GR complexes, following geometry optimization, docking, and RESP charge fitting. The results show that the presence and nature of the amino group and its substituent crucially influence the ligand’s ability to approach the GR active site, with compound 2b achieving a favorable orientation toward SCys-58 while 1b fails and 3b is hindered by a bulky substituent. Overall, MD reveals dynamic, orientation-dependent interactions that complement prior docking studies and indicate a real possibility for RSeSG reduction at GR, informing design strategies for enhanced GPx-mimic activity.

Abstract

In the search for small organoselenium-based mimics of the glutathione peroxidase (GPx) enzyme, it has been observed that selenenyl sulfides (RSeSG) derived from amine-based GPx mimics have the potential to be reduced at the catalytic site of glutathione reductase (GR), thereby enhancing the catalytic efficiency of these mimics in biological systems. However, molecular insights into these interactions are lacking due to the absence of force field parameters for Se-S containing compounds. In this study, we present force field parameters for selenenyl sulfides with a phenyl selenide backbone developed using the General Amber Force Field (GAFF). Employing these parameters, a 200 ns molecular dynamics (MD) simulation of RSeSG was performed. The results indicate that both the amino nitrogen and its substituent significantly influence the interaction of RSeSG at the catalytic site of GR.

Paper Structure

This paper contains 7 sections, 2 equations, 3 figures, 1 table.

Table of Contents

  1. Introduction
  2. Computational methods
  3. Results and Discussion
  4. GAFF parameters for RSeSG
  5. Validation of the derived GAFF parameters
  6. Testing of the derived GAFF parameters
  7. Conclusion

Figures (3)

  • Figure 1: The catalytic cycle of GPx mimics in biological assay. Disulfides (GSSG) generated during the catalytic cycle are converted to glutathione (GSH) using glutathione reductase (GR) enzyme.
  • Figure 2: Structures of the compounds studied.
  • Figure 3: Heavy-atom RMSD of the ligand relative to protein backbone (top left), radius of gyration for protein backbone and ligand (top right), solvent-accessible surface area (SASA) of the protein–ligand complex (bottom left), and RMSF of both protein backbone and ligand (bottom right).