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. 2022 Apr 22;23(9):4629.
doi: 10.3390/ijms23094629.

The Use of Molecular Dynamics Simulation Method to Quantitatively Evaluate the Affinity between HBV Antigen T Cell Epitope Peptides and HLA-A Molecules

Xueyin Mei  1 , Xingyu Li  1 , Chen Zhao  2 , Anna Liu  1 , Yan Ding  2 , Chuanlai Shen  2 , Jian Li  1
Affiliations

The Use of Molecular Dynamics Simulation Method to Quantitatively Evaluate the Affinity between HBV Antigen T Cell Epitope Peptides and HLA-A Molecules

Xueyin Mei et al. Int J Mol Sci. .

Abstract

Chronic hepatitis B virus (HBV), a potentially life-threatening liver disease, makes people vulnerable to serious diseases such as cancer. T lymphocytes play a crucial role in clearing HBV virus, while the pathway depends on the strong binding of T cell epitope peptide and HLA. However, the experimental identification of HLA-restricted HBV antigenic peptides is extremely time-consuming. In this study, we provide a novel prediction strategy based on structure to assess the affinity between the HBV antigenic peptide and HLA molecule. We used residue scanning, peptide docking and molecular dynamics methods to obtain the molecular docking model of HBV peptide and HLA, and then adopted the MM-GBSA method to calculate the binding affinity of the HBV peptide-HLA complex. Overall, we collected 59 structures of HLA-A from Protein Data Bank, and finally obtained 352 numerical affinity results to figure out the optimal bind choice between the HLA-A molecules and 45 HBV T cell epitope peptides. The results were highly consistent with the qualitative affinity level determined by the competitive peptide binding assay, which confirmed that our affinity prediction process based on an HLA structure is accurate and also proved that the homologous modeling strategy for HLA-A molecules in this study was reliable. Hence, our work highlights an effective way by which to predict and screen for HLA-peptide binding that would improve the treatment of HBV infection.

Keywords: MM-GBSA; affinity; hepatitis B virus; molecular dynamics; residue scanning.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Modelled structure docking model. Ligands for modelled receptor structures and modelled template structures are shown in gray and predictive ligands are colored in magenta. (A) HLA-A * 11:02 (B) HLA-A * 26:01 (C) HLA-A * 31:01 (D) HLA-A * 33:03.
Figure 2
Figure 2
A 2D structure of the interaction between peptide and HLA structure. Residues are represented by the shape of water droplets. The interactions between residues and ligands are represented by lines and colored according to different interaction types. The hydrogen bond is colored in magenta and the Pi-Pi bond is colored in green. Magenta gradient lines represent salt bridge. (A) Interaction of HLA-A * 02:01 (PDB ID: 1JHT) and its peptide (ALGIGILTV). Hydrogen bonds are formed between peptide and amino acids TYR7, GLU63, LYS66, ASP77, TYR84, TYR99, THR143, LYS146, TRP147, TYR159 and TYR171. A salt bridge is formed with residue LYS146. (B) Interaction of HLA-A * 02:01 (PDB ID: 1JHT) and HBV-positive peptide (FLWEWASVR). Hydrogen bonds are formed between peptide and amino acids TYR7, GLU63, LYS66, ASP77, TYR84, ARG97, TYR99, THR143, TRP147, GLU155, TYR159 and TYR171, Pi-Pi bond is formed with residue TYR159 and salt bridges are formed with residue ARG65, ASP77 and LYS146. (C) Interaction of HLA-A * 24:02 (PDB ID: 5XWD) and its peptide (LYKKLKREMTF). Hydrogen bonds are formed between peptide and amino acids TYR7, GLU63, LYS66, HIE70, ASN77, TYR84, LYS146, TRP147, TYR159 and TYR171, Pi-Pi bonds are formed with residue PHE99 and TYR116, salt bridge is formed with residue GLU63. (D) Interaction of HLA-A * 24:02 (PDB ID: 5XWD) and HBV positive peptide (VWLSVIWMMW). Hydrogen bonds are formed between peptide and amino acids TYR7, GLU63, LYS66, ASN77, TYR84, LYS146, TRP147, GLU155, TYR159 and TYR171, Pi-Pi bonds are formed with residue PHE99, TYR116 and TYR123, salt bridge is formed with residue GLU63. (E) Interaction of HLA-A * 02:01 (PDB ID: 3UTQ) and its peptide (ALWGPDPAAA). Hydrogen bonds are formed between peptide and amino acids TYR7, GLU63, LYS66, THR73, ASP77, TYR99, THR143, LYS146, TRP147, TYR159 and TYR171, salt bridge is formed with residue LYS146. (F) Interaction of HLA-A * 02:01 (PDB ID: 3UTQ) and HBV positive peptide (ETVLEYLVSV). Hydrogen bonds are formed between peptide and amino acids TYR7, GLU63, ARG65, LYS66, THR73, ASP77, TYR84, TYR99, THR143, TRP147, TYR159 and TYR171, and salt bridges are formed with residue GLU63, ARG65, LYS66 and LYS146.
Figure 3
Figure 3
RMSD of the docking structure. The arrow (red) indicates the selected stable regions, where the value fluctuates slightly and can be used for subsequent calculations of the binding free energy. (A) The complex 5GRD-SMYPSCCCTK remained stable between 10 and 100 ns. (B) The complex 1I4F-SMYPSCCCTK remained stable from 80 to 100 ns. (C) The complex 3RL2-SMYPSCCCTK remained stable between 60 and 100 ns. (D) Compound A * 26:01-ETVLEYLVSV remained stable from 60 to 100 ns. (E) Compound 5GRD-ETVLEYLVSV remained stable from 60 to 100 ns. (F) Compound 3UTQ-ETVLEYLVSV remained stable from 20 to 100 ns.
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