Abstract
The immune system is constantly challenged, being required to protect the organism against a wide variety of infectious pathogens and, at the same time, to avoid autoimmune disorders. One of the most important molecules involved in these events is the Major Histocompatibility Complex class I (MHC-I), responsible for binding and presenting small peptides from the intracellular environment to CD8+ T cells. The study of peptide:MHC-I (pMHC-I) molecules at a structural level is crucial to understand the molecular mechanisms underlying immunologic responses. Unfortunately, there are few pMHC-I structures in the Protein Data Bank (PDB) (especially considering the total number of complexes that could be formed combining different peptides), and pMHC-I modelling tools are scarce. Here, we present DockTope, a free and reliable web-based tool for pMHC-I modelling, based on crystal structures from the PDB. DockTope is fully automated and allows any researcher to construct a pMHC-I complex in an efficient way. We have reproduced a dataset of 135 non-redundant pMHC-I structures from the PDB (Cα RMSD below 1 Å). Modelling of pMHC-I complexes is remarkably important, contributing to the knowledge of important events such as cross-reactivity, autoimmunity, cancer therapy, transplantation and rational vaccine design.
Highlights
In this work we described a fully automated tool for the structural prediction of peptide:Major Histocompatibility Complex class I (MHC-I) complexes, DockTope, which was developed and validated for the MHC-I allotypes HLA-A*02:01, HLA-B*27:05, H-2-Kb and H-2-Db
Target and model were always fitted by MHC-I residues, which ensures that the difference between each epitope residue pair is considered, and its displacement inside the MHC-I cleft after the molecular docking/energy minimization process
DockTope performs a total of 20 rounds of molecular docking, generating up to 1000 conformations, which increases the probability of finding a proper epitope conformation
Summary
Despite the availability of homology modelling techniques, each allotype presents specific particularities that cannot be determined through regular approaches. We present DockTope, a fully automated web-server tool designed with the purpose of modelling pMHC-I complexes for two human (HLA-A*02:01 and HLA-B*27:05) and two murine (H-2-Db and H-2-Kb) MHC-I allotypes. We have validated this tool through the cross-docking reproduction of 135 non-redundant structurally resolved pMHC-I structures available in the Protein Data Bank (PDB), using Cα and all atom Root Mean Square Deviation (RMSD) values for evaluation. We have designed a dedicated web server providing free and easy access to any user throughout the world
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