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Designing high affinity target-binding peptides to HLA-E: a key membrane antigen of multiple myeloma.

ABSTRACT: Multiple myeloma (MM) is a plasma cell malignancy that is currently incurable. Finding new targets and designing drugs are crucial for the treatment of MM. The two datasets (GSE6691 and GSE39754) are used to screen highly expressed antigen on MM cells. HLA-E was an ideal target for it was a hub gene, and also located in one of the key clusters. Highly expression of HLA-E mRNA on MM cells was also confirmed by real-time qPCR testing the MM patients' samples in Shengjing hospital. Crystal structure of HLA-E was obtained from Protein Data Bank (PDB ID: 3CDG) which was used to design targeting peptides with Molecular Operating Environment software. By analyzing interaction between CD94/NKG2A and HLA-E, a peptide with twelve amino acids was screened as a model peptide. Peptides library was constructed by randomly replaced non-key amino acid. Peptide-protein docking method was used to identify high affinity peptides. PEPTIDE 1-3 and model peptide were synthesized and identified the affinity to HLA-E by flow cytometer and confocal laser microscopy. At last, PEPTIDE3 (NALDEYCEDKNR) was found with the highest affinity. Taking all, HLA-E is a new treatment target, and PEPTIDE 3 is an ideal high affinity target-binding peptide candidate.

SUBMITTER: Yang Y

PROVIDER: S-EPMC7655190 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Designing high affinity target-binding peptides to HLA-E: a key membrane antigen of multiple myeloma.

Yang Ying Y Sun Mingli M Yu Zhaojin Z Liu Jinwei J Yan Wei W Liu Zhuogang Z Wei Minjie M Wang Hongtao H

Aging 20201028 20

Multiple myeloma (MM) is a plasma cell malignancy that is currently incurable. Finding new targets and designing drugs are crucial for the treatment of MM. The two datasets (GSE6691 and GSE39754) are used to screen highly expressed antigen on MM cells. HLA-E was an ideal target for it was a hub gene, and also located in one of the key clusters. Highly expression of HLA-E mRNA on MM cells was also confirmed by real-time qPCR testing the MM patients' samples in Shengjing hospital. Crystal structur ...[more]

PMID: 33115963

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Project description:BackgroundMajor histocompatibility complex class I (MHC-I) plays an important role in cell immune response, and stable interaction between polypeptides and MHC-I ensures efficient presentation of polypeptide-MHC-I (pMHC-I) molecular complexes to T cells. The aim of this study was to explore ways to improve the affinity and stability of the p-Human Leukocyte Antigen (HLA)-A*2402 complex.MethodsThe peptide sequences of the restricted antigen peptides for HLA-A*2402 and the results of the in vitro competitive binding test were retrieved from the literature. The affinity values were predicted using NetMHCpan v4.1 server, and the stability values were predicted using the NetMHCstab v1.0 server. Auto Vina was used to dock peptides to HLA-A*2402 protein in a flexible docking manner, while Flexpepdock was employed to optimize the docking morphology. Maestro was used to analyze the intermolecular forces and the binding affinity of the complex, while MM-GBSA was used to calculate the binding free energy values.ResultsThe intermolecular interactions that maintained the affinity and stability of peptide-HLA-A*2402 complex relied mainly on HB, followed by pi stack. The binding affinity values of molecular docking were associated with the predicted values of affinity and stability, the binding affinity and the binding free energy, as well as the intermolecular force pi-stack. The pi stack had a significant negative correlation with binding affinity and binding free energy. The replacement of the residues of the polypeptides that did not form pi-stack interactions with HLA-A*2402 improved the affinity and/or stability compared to before replacement.ConclusionsThe generation and increase in the number of pi-stacks between peptides and HLA-A*2402 molecules may help improve the affinity and stability of p-HLA-A*2402 complexes. The prediction of intermolecular forces and binding affinity of peptide-HLA by means of molecular docking is a supplement to the current commonly used prediction databases.

Dataset Information

Designing high affinity target-binding peptides to HLA-E: a key membrane antigen of multiple myeloma.

Publications

Designing high affinity target-binding peptides to HLA-E: a key membrane antigen of multiple myeloma.

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