pDOCK: a new technique for rapid and accurate docking of peptide ligands to Major Histocompatibility Complexes

Khan and Ranganathan Immunome Research 2010, 6(Suppl 1):S2 http://www.immunome-research.com/content/6/S1/S2 IMMUNOME RESEARCH PROCEEDINGS Open Access pDOCK: a new technique for rapid and accurate docking of peptide ligands to Major Histocompatibility Complexes Javed Mohammed Khan1, Shoba Ranganathan1,2* From Asia Pacific Bioinformatics Network (APBioNet) Ninth International Conference on Bioinformatics (InCoB2010) Tokyo, Japan. 26-28 September 2010 Abstract Background: Identification 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. Results: We 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 Ca 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 Ca 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. Conclusions: The 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. * Correspondence: 1 Department of Chemistry and Biomolecular Sciences and ARC Center of Excellence in Bioinformatics, Macquarie University, NSW 2109, Australia Full list of author information is available at the end of the article © 2010 Ranganathan and Khan; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Khan and Ranganathan Immunome Research 2010, 6(Suppl 1):S2 http://www.immunome-research.com/content/6/S1/S2 Background 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. 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. Peptide epitopes can be of endogenous (processed within the cell) or exogenous (processed outside the cell) origins, which are presented for surveillance and recognition by the TR in an MHC allele and supertype dependant manner. Broadly classified into two types, MHC class I (MHC-I) complexes bind and present endogenous peptides whereas MHC class II (MHC-II) complexes prefer exogenous peptides. Typically, MHC-I proteins are heterodimers, consisting of a heavy a chain (IALPHA) of about 45 kDa, and a light chain, b2-microglobulin (Β2M) of about 12 kDa [2,3]. The a chain consists of a1 (G-ALPHA1), a2 (G-ALPHA2) and a3 (C-LIKE) domains where G-ALPHA1 and G-ALPHA2 domains form the peptide binding groove or ‘cleft’ [4]. MHC-II proteins are also 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 [5-10]. However, their peptide binding groove is formed by the a1 and b1 domains of the two chains. Peptides presented by MHC-I are generally between 811 amino acids in length. These peptides are ‘chopped’ within the cytosol of the cell by cytosolic proteases and are transported to the MHC binding groove within the endoplasmic reticulum by the transporters associated with antigen processing (TAP) proteins in an ATP dependant manner. Following which, the peptides bind to the MHC to form the peptide-MHC (pMHC) complex which is then transported to the APC cell surface and presented for recognition by the TR of CD8+ cytotoxic T cells (CTLs). Similarly, the peptides presented by MHC-II are usually 12-25 amino acids in length and are endocytosed into the cell by the lysosomes where they bind the MHC-II proteins by displacing the original MHC-II ligand known as the ‘CLIP’ peptide to form the pMHC complex. And again, they are transported to the APC cell surface for recognition by the TR of the CD4+ T helper cells. Identification of true T cell epitopes from the repertoires of immunologically significant antigenic peptide sequences is a vital prerequisite in the process of conventional molecular vaccine design for prevention and treatment of infectious, autoimmune, allergic and graft vs. host diseases. The key step in TR-mediated immune response is thus the binding and presentation Page 2 of 16 of antigenic endogenous or exogenous peptide epitopes, which can be reasonably well predicted using sequencebased methods for alleles with large datasets of known binding peptides, as reviewed earlier [11,12]. Experimental identification of T cell epitopes is a tedious, time consuming and expensive process owing to the large number and diversity of both MHC alleles and the antigenic peptides. Not to mention, is the extremely low chance of immunogenicity (1 in 2000 peptides) even amongst the peptides that bind strongly to the MHC (50%) [13]. Recently developed computational methods have proven to be vastly time and cost efficient in screening th (...truncated)