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Tripathi, Sunil Kumar and Salunke, Dinakar M. (2020) Exploring the different states of wild-type T-cell receptor and mutant conformational changes towards understanding the antigen recognition. Journal of Biomolecular Structure and Dynamics. pp. 1-14. ISSN 0739-1102

Exploring the Different States of Wild-Type T-cell Receptor and Mutant Conformational Changes Towards Understanding the Antigen Recognition.pdf

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Recognition of proteolytic peptide fragments presented by major histocompatibility complex (MHC) on target cells by T-cell receptor (TCR) is among the most important interactions in the adaptive immune system. Several computational studies have been performed to investigate conformational and dynamical properties of TCRs for enhanced immunogenicity. Here, we present the large-scale molecular dynamics (MD) simulation studies of the two comprehensive systems consisting of the wildtype and mutant IG4 TCR in complex with the tumor epitope NY-ESO peptide (SLLMWITQC) and analyzed for mapping conformational changes of TCR in the states prior to antigen binding, upon antigen binding and after the antigen was released. All of the simulations were performed with different states of TCRs for each 1000 ns of simulation time, providing six simulations for time duration of 6000 ns (6ms). We show that rather than undergoing most critical conformational changes upon antigen binding, the high proportion of complementarity-determining region (CDR) loops change by comparatively small amount. The hypervariable CDRa3 and CDRb3 loops showed significant structural changes. Interestingly, the TCR b chain loops showed the least changes, which is reliable with recent implications that b domain of TCR may propel antigen interaction. The mutant shows higher rigidity than wild-type even in released state; expose an induced fit mechanism occurring from the re-structuring of CDRa3 loop and can allow enhanced binding affinity of the peptide antigen. Additionally, we show that CDRa3 loop and peptide contacts are an adaptive feature of affinity enhanced mutant TCR.

Item Type: Article
Subjects: Biochemical and Biophysical Sciences
Depositing User: RCB Library
Date Deposited: 21 Jun 2022 05:58
Last Modified: 21 Jun 2022 05:58
URI: http://rcb.sciencecentral.in/id/eprint/245

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