TY - JOUR
T1 - PDOCK
T2 - a new technique for rapid and accurate docking of peptide ligands to Major Histocompatibility Complexes
AU - Khan, Javed Mohammed
AU - Ranganathan, Shoba
N1 - This version is archived for private and non-commercial use under the terms of this BioMed Central open access license ("license") (see http://www.biomedcentral.com/info/about/license). The work is protected by copyright and/or other applicable law. Any use of the work other than as authorized under this license is prohibited. For further rights please check the terms of the license, or contact the publisher.
PY - 2010
Y1 - 2010
N2 - 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 C RMSD of less than 1.00 , with a mean of 0.56 . Amongst the 25 peptides used for single and variant template docking, the C RMSD values were below 1.00 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.
AB - 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 C RMSD of less than 1.00 , with a mean of 0.56 . Amongst the 25 peptides used for single and variant template docking, the C RMSD values were below 1.00 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.
UR - http://www.scopus.com/inward/record.url?scp=77957258599&partnerID=8YFLogxK
U2 - 10.1186/1745-7580-6-S1-S2
DO - 10.1186/1745-7580-6-S1-S2
M3 - Article
C2 - 20875153
AN - SCOPUS:77957258599
SN - 1745-7580
VL - 6
SP - 1
EP - 16
JO - Immunome Research
JF - Immunome Research
IS - SUPPL. 1
M1 - S2
ER -