Steroid hormone binding and modulation of Trichinella spiralis progesterone receptor: A computational approach

Abstract

Trichinellosis, caused by Trichinella species, including Trichinella spiralis, is a foodborne zoonotic disease. Upon ingestion, ML swiftly invade the intra-multicellular niche of the small intestine, undergoing four rapid molts to mature into adults. In general, the route of transmission for T. spiralis nematodes occurs through ingestion of pork. Therefore, it is crucial to develop a vaccine that can deal with trichinellosis, particularly for humans and pigs. In this study, homology modelling, molecular docking, simulations and molecular mechanics-based scoring (MM/GBSA) are used to investigate the interaction between T. spiralis membrane-associated progesterone receptor component 2 (Ts-MAPRC2) and different steroids hormones. In the most favorable region, 93 amino acid residues (92.1 %) are located, while 7 amino acids (6.9 %) are located in the allowed region, showing that the model with a 93.33 ERRAT quality factor is good quality. The MD simulations were conducted for 50 ns to explore the affinities and stability of four hormones chosen from the docking studies that showed similar binding poses to the control hormone Mifepristone. Simulations showed that the selected hormones were potent Ts-MAPRC2 binders and can act as leads to determine their activity by biophysical assays. Discovery of these five steroid hormones and interactions with Ts-MAPRC2 could lead to new therapies and vaccines for trichinellosis.

Keywords: Molecular modeling; Simulation; Steroid hormones; Trichinella spiralis; Ts-MAPRC2.

Fig. 1

(A) Ramachandran Plot: The plot reveals that 92.1 % of the residues are located within the most favored regions (depicted in red), while 6.9 % of the residues fall within additionally allowed regions (yellow). Notably, no residues were found in the disallowed regions (white), indicating favorable stereochemical quality of the modeled structure. (B) ERRAT Quality Factor: The ERRAT quality chart was used to assess the overall model reliability based on non-bonded atomic interactions.

Fig. 2

The re-docking of 17β-estradiol into the protein binding pocket. The blue stick representation denotes the initially docked conformation, while the red ball-and-stick model represents the re-docked conformation.

Fig. 3

The binding modes and interactions of the selected hormones. (A) 17-Estradiol (B) Aglepristone (C) Mifepristone (D) Norepinephrine (E) Prostaglandins. Subsequently, these hormones were docked into the predicted binding site of the target protein Ts-MAPRC2 to assess potential interactions.The three-dimensional structure is displayed at the center, offering a comprehensive representation of the interactions involved.

Fig. 4

The RMSD plots of backbone of Ts-MAPRC2 protein complexed with hormones. The RMSD plots of ligands docked with the Ts-MAPRC2protein. All systems are distinguished by color coding as follows: blue for Ts-MAPRC2–Norepinephrine, red for Aglepristone, turquoise for 17β-Estradiol, yellow for Prostaglandins, green for Mifepristone, and black for the ligand.

Fig. 5

Simulating Ts-MAPRC2 complexes and analyzing residual flexibility.Each system is distinguished by a specific color code: blue for Ts-MAPRC2-Norepinephrine, red for Ts-MAPRC2-Aglepristone, turquoise for Ts-MAPRC2-17β-Estradiol, yellow for Ts-MAPRC2-Prostaglandins, and green for Ts-MAPRC2-Mifepristone.

Fig. 6

The protein compactness analysis of Ts-MAPRC2 complexes by calculating Radius of Gyration. Each system is distinguished by a specific color code: blue for Ts-MAPRC2-Norepinephrine, red for Ts-MAPRC2-Aglepristone, turquoise for Ts-MAPRC2-17β-Estradiol, yellow for Ts-MAPRC2-Prostaglandins, and green for Ts-MAPRC2-Mifepristone.

Fig. 7

The solvent-accessible surface area calculation of Ts-MAPRC2 complexes.Each system is distinguished by a specific color code: blue for Ts-MAPRC2-Norepinephrine, red for Ts-MAPRC2-Aglepristone, turquoise for Ts-MAPRC2-17β-Estradiol, yellow for Ts-MAPRC2-Prostaglandins, and green for Ts-MAPRC2-Mifepristone.

Fig. 8

Binding energy decomposition analysis of the complexes to identify key interacting residues.