Intramolecular Domain Movements of Free and Bound pMHC and TCR Proteins: A Molecular Dynamics Simulation Study

Abstract

The interaction of antigenic peptides (p) and major histocompatibility complexes (pMHC) with T-cell receptors (TCR) is one of the most important steps during the immune response. Here we present a molecular dynamics simulation study of bound and unbound TCR and pMHC proteins of the LC13-HLA-B*44:05-pEEYLQAFTY complex to monitor differences in relative orientations and movements of domains between bound and unbound states of TCR-pMHC. We generated local coordinate systems for MHC α1- and MHC α2-helices and the variable T-cell receptor regions TCR Vα and TCR Vβ and monitored changes in the distances and mutual orientations of these domains. In comparison to unbound states, we found decreased inter-domain movements in the simulations of bound states. Moreover, increased conformational flexibility was observed for the MHC α2-helix, the peptide, and for the complementary determining regions of the TCR in TCR-unbound states as compared to TCR-bound states.

Genomic Diversity of the Major Histocompatibility Complex in Health and Disease

“…The 18 papers gathered together in this Special Issue highlight the enormous genetic diversity and broad complexity of the MHC regulatory system and why its genomic structure and function is continuously under scientific investigation. These articles provide new insights as well as confirm some of the more tenuous and/or established beliefs about the genetic and biological roles of the MHC [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]. More importantly, many of these articles point MHC researchers and scholars in new directions where technical developments and research can greatly improve our knowledge and concepts of the structure and function of the MHC genomic region, especially as functional haplotypes in humans and all the other vertebrate species on the planet that thrive or are in danger of extinction.…”

“…Five research papers are specifically on the topic of MHC antigen presentation and/or interactions with receptors of T cells or killer cells in health or disease [23,24,25,27,28]. One research paper focusses on haplotyping Class II genes using SNPs associated with disease [26], whereas another examines the importance of MHC Class I gene expression on spinal motoneuron survival and glial reaction following a spinal ventral root crush in wild type and beta2-microglobulin knockout mice [29].…”

“…The response is driven by TCRs specifically recognising antigenic peptides bound to and presented by the MHC molecules of infected or transformed cells [12,13]. In this Special Issue, Karch and co-workers presented a molecular dynamics simulation study of bound and unbound TCR and pMHC proteins of the LC13-HLA-B*44:05-pEEYLQAFTY complex to monitor differences in relative orientations and movements of domains between bound and unbound states of TCR-pMHC [23]. They found decreased inter-domain movements in the simulations of bound states when compared to unbound states; and increased conformational flexibility was observed for the MHC alpha-2-helix, the peptide, and for the complementary determining regions of the TCR in TCR-unbound states as compared to TCR-bound states.…”

“…This Special Issue on the “Genomic Diversity of the MHC in Health and Disease” consists of eighteen papers with one commentary [16], five reviews [17,18,19,20,21], eleven research articles [22,23,24,25,26,27,28,29,30,31,32] and one communication [33]. These papers cover a broad range of topics on the genomic diversity of the MHC regulatory system in various vertebrate species in health and disease including structure and function; MHC Class I, II and III genes; antigen presentation; innate and adaptive immunity; neurology; transplantation; haplotypes; alleles; infectious and autoimmune diseases; fecundity; conservation; lineage; and evolution.…”

Flexibility-aware graph-based algorithm improves antigen epitopes identification

“…Protein flexibility has been widely reported, and there are three types of flexibility, i.e., local flexibility (at atom/residue level) [16], regional flexibility (at intra-domain/multi-residue level) [17], and global flexibility (at multi-domain level) [18]. The local and regional flexibility are mainly caused by the movement of chemical bonds and bond angles [19], while the global flexibility mostly comes from the hinges, helical-to-extended conformations and side chains [20][21][22]. Taking as an example shown in Fig 1, the two structures (having the Protein Data Bank (PDB) [23] identifier of 1A14 and 7NN9, respectively) have exactly the same sequence of residues, but notably different structures after aligned.…”