Abstract
BackgroundIdentification of antigenic peptide epitopes is an essential prerequisite in T cell-based molecular vaccine design. Computational (sequence-based and structure-based) methods are inexpensive and efficient compared to experimental approaches in screening numerous peptides against their cognate MHC alleles. In structure-based protocols, suited to alleles with limited epitope data, the first step is to identify high-binding peptides using docking techniques, which need improvement in speed and efficiency to be useful in large-scale screening studies. We present pDOCK: a new computational technique for rapid and accurate docking of flexible peptides to MHC receptors and primarily apply it on a non-redundant dataset of 186 pMHC (MHC-I and MHC-II) complexes with X-ray crystal structures.ResultsWe have compared our docked structures with experimental crystallographic structures for the immunologically relevant nonameric core of the bound peptide for MHC-I and MHC-II complexes. Primary testing for re-docking of peptides into their respective MHC grooves generated 159 out of 186 peptides with Cα RMSD of less than 1.00 Å, with a mean of 0.56 Å. Amongst the 25 peptides used for single and variant template docking, the Cα RMSD values were below 1.00 Å for 23 peptides. Compared to our earlier docking methodology, pDOCK shows upto 2.5 fold improvement in the accuracy and is ~60% faster. Results of validation against previously published studies represent a seven-fold increase in pDOCK accuracy. ConclusionsThe limitations of our previous methodology have been addressed in the new docking protocol making it a rapid and accurate method to evaluate pMHC binding. pDOCK is a generic method and although benchmarks against experimental structures, it can be applied to alleles with no structural data using sequence information. Our outcomes establish the efficacy of our procedure to predict highly accurate peptide structures permitting conformational sampling of the peptide in MHC binding groove. Our results also support the applicability of pDOCK for in silico identification of promiscuous peptide epitopes that are relevant to higher proportions of human population with greater propensity to activate T cells making them key targets for the design of vaccines and immunotherapies.
Highlights
Identification of antigenic peptide epitopes is an essential prerequisite in T cell-based molecular vaccine design
The molecular machinery by which an antigen presenting cell (APC) presents T cell epitopes for recognition by T cell receptors (TR) and subsequent activation of T cells followed by the immune response cascade is fascinating
A systematic evaluation of peptide docking method (pDOCK) is performed as three separate tests: (1) exhaustive re-docking of all non-redundant peptides to their respective major histocompatibility complexes (MHC) grooves as a test case, benchmarking and validation; we address two very significant practical problems faced by immunologists during the process of allele-specific peptide vaccine design: (2) the docking of multiple peptides that bind to same MHC allele, for immunogenic epitope scanning of antigenic sequences and; (3) docking of promiscuous peptides or same peptides binding to multiple MHC alleles for vaccine design, based on groups of disease-implicated alleles
Summary
Identification of antigenic peptide epitopes is an essential prerequisite in T cell-based molecular vaccine design. T cell epitopes are short antigenic peptide sequences (p) that are bound to and presented by the major histocompatibility complexes (MHC) for recognition by the TR [1]. These epitopes are essential subunit peptides that are required in order to stimulate cellular immune responses, especially the adaptive immune responses. MHC-II proteins are heterodimeric proteins consisting of an a chain (IIAPLHA; 34 kDa) and a b chain (II-BETA; 29 kDa) with very similar overall quaternary structure to that of MHC-I proteins [5,6,7,8,9,10] Their peptide binding groove is formed by the a1 and b1 domains of the two chains
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