Abstract
Peripheral T-cell lymphoma (PTCL) is a type of non-Hodgkin lymphoma that progresses aggressively with poor survival rate. CAR T cell targeting T-cell receptor β-chain constant domains 1 (TRBC1) of malignant T cells has been developed recently by using JOVI.1 monoclonal antibody as a template. However, the mode of JOVI.1 binding is still unknown. This study aimed to investigate the molecular interaction between JOVI.1 antibody and TRBC1 by using computational methods and molecular docking. Therefore, the TRBC protein crystal structures (TRBC1 and TRBC2) as well as the sequences of JOVI.1 CDR were chosen as the starting materials. TRBC1 and TRBC2 epitopes were predicted, and molecular dynamic (MD) simulation was used to visualize the protein dynamic behavior. The structure of JOVI.1 antibody was also generated before the binding mode was predicted using molecular docking with an antibody mode. Epitope prediction suggested that the N3K4 region of TRBC1 may be a key to distinguish TRBC1 from TCBC2. MD simulation showed the major different surface conformation in this area between two TRBCs. The JOVI.1-TRBC1 structures with three binding modes demonstrated JOVI.1 interacted TRBC1 at N3K4 residues, with the predicted dissociation constant (Kd) ranging from 1.5 × 108 to 1.1 × 1010 M. The analysis demonstrated JOVI.1 needed D1 residues of TRBC1 for the interaction formation to N3K4 in all binding modes. In conclusion, we proposed the three binding modes of the JOVI.1 antibody to TRBC1 with the new key residue (D1) necessary for N3K4 interaction. This data was useful for JOVI.1 redesign to improve the PTCL-targeting CAR T cell.
Highlights
Peripheral T-cell lymphoma (PTCL) is a type of non-Hodgkin lymphoma that progresses aggressively with poor survival rate
TRBC1, but not TRBC2, we tried to identify which TRBC1 antigenic determinant can be the selective residues for the antibody
TRBC1 and TRBC2 sequences showed that four amino acids are found to be conserved for each TRBC, including N3, K4, E9 and F36 for TRBC1, and K3, N4, K9 and Y36 for TRBC2 (Fig. 1A)
Summary
Peripheral T-cell lymphoma (PTCL) is a type of non-Hodgkin lymphoma that progresses aggressively with poor survival rate. We proposed the three binding modes of the JOVI.[1] antibody to TRBC1 with the new key residue (D1) necessary for N3K4 interaction This data was useful for JOVI.[1] redesign to improve the PTCL-targeting CAR T cell. To investigate the selective binding of JOVI.[1] with the TRBC counterparts, the computational modeling approaches such as molecular docking and molecular dynamics simulation were introduced. These methods were proven to be successful in various molecular predictions such as drug-protein c omplexes[9,10,11] and antibody design[12,13]. We investigated the JOVI.1-TRBC complex to propose its binding mode and binding selectivity via homology modeling and molecular docking
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