Ying Zhu1, Chang-Xin Huang2, Le Zhang3, Ze-Fang Wang4, Dong-Li Zhao3, Fei Ding2, Si-Yu Zhang2, Yong-Qiang Li2, Ling-Zhi Chen5. 1. Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University Hangzhou 310000, Zhejiang, China. 2. Department of Oncology, The Affiliated Hospital of Hangzhou Normal University Hangzhou 310000, Zhejiang, China. 3. Master Class, Zhejiang Chinese Medical University, The Fourth School of Clinical Medicine Hangzhou 310000, Zhejiang, China. 4. Master Class, Hangzhou Normal University, The School of Medicine Hangzhou 3100000, Zhejiang, China. 5. Department of Blood Transfusion, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University Jiaxing 314000, Zhejiang, China.
Abstract
OBJECTIVE: This study aims to investigate the use of single residue substitution to promote the formation of pi-stacking interactions between peptides and Human leukocyte antigen (HLA)-A*2402 molecules to improve the affinity of peptides and HLA molecules, as well as the level of cytotoxic T lymphocyte (CTL) cells activated by peptides-HLA (p-HLA) complex. METHODS: Molecular docking and molecular dynamics simulation were used to simulate and analyze the interactions and binding free energies between HLA-A*2402-restricted antigen peptides and HLA molecules, before and after the single residue substitution. HLA-A*2402 restricted antigen peptides before and after the single residue replacement were loaded into dendritic cells (DCs) in vitro, and further Enzyme-Linked ImmunoSpot (ELispot) test was carried out to evaluate the effect of modified antigen peptides on the immune activation of CTL cells. RESULT: After replacing the antigen peptides with a single residue, some of them could promote the formation of pi-stacking interaction. The binding free energy between the modified antigen peptides and HLA-A*2402, as well as the level of immune activation of CTL cells were mostly higher than before, especially after the replacement of the 9th residue of the polypeptide, such as C9F and C9W. There was a significant negative correlation between the level of activated CTL cells by modified antigen peptides and the total interaction amount of hydrogen bonds and salt bridges. CONCLUSION: Promoting the formation of pi-stacking interaction between antigen peptides and HLA-A*2402 molecules could increase the total binding free energy of p-HLA complex and the level of CTL cells activation. In addition, the amount of hydrogen bonds and salt bridges between peptides and HLA could reduce the level of immune activation. All the characteristics above can improve the immunogenicities of the weak antigens. AJTR
OBJECTIVE: This study aims to investigate the use of single residue substitution to promote the formation of pi-stacking interactions between peptides and Human leukocyte antigen (HLA)-A*2402 molecules to improve the affinity of peptides and HLA molecules, as well as the level of cytotoxic T lymphocyte (CTL) cells activated by peptides-HLA (p-HLA) complex. METHODS: Molecular docking and molecular dynamics simulation were used to simulate and analyze the interactions and binding free energies between HLA-A*2402-restricted antigen peptides and HLA molecules, before and after the single residue substitution. HLA-A*2402 restricted antigen peptides before and after the single residue replacement were loaded into dendritic cells (DCs) in vitro, and further Enzyme-Linked ImmunoSpot (ELispot) test was carried out to evaluate the effect of modified antigen peptides on the immune activation of CTL cells. RESULT: After replacing the antigen peptides with a single residue, some of them could promote the formation of pi-stacking interaction. The binding free energy between the modified antigen peptides and HLA-A*2402, as well as the level of immune activation of CTL cells were mostly higher than before, especially after the replacement of the 9th residue of the polypeptide, such as C9F and C9W. There was a significant negative correlation between the level of activated CTL cells by modified antigen peptides and the total interaction amount of hydrogen bonds and salt bridges. CONCLUSION: Promoting the formation of pi-stacking interaction between antigen peptides and HLA-A*2402 molecules could increase the total binding free energy of p-HLA complex and the level of CTL cells activation. In addition, the amount of hydrogen bonds and salt bridges between peptides and HLA could reduce the level of immune activation. All the characteristics above can improve the immunogenicities of the weak antigens. AJTR
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