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Deciphering complex patterns of class-I HLA-peptide cross-reactivity via hierarchical grouping

Mukherjee, Sumanta and Warwicker, Jim and Chandra, Nagasuma (2015) Deciphering complex patterns of class-I HLA-peptide cross-reactivity via hierarchical grouping. In: IMMUNOLOGY AND CELL BIOLOGY, 93 (6). pp. 522-532.

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Official URL: http://dx.doi.org/10.1038/icb.2015.3


T-cell responses in humans are initiated by the binding of a peptide antigen to a human leukocyte antigen (HLA) molecule. The peptide-HLA complex then recruits an appropriate T cell, leading to cell-mediated immunity. More than 2000 HLA class-I alleles are known in humans, and they vary only in their peptide-binding grooves. The polymorphism they exhibit enables them to bind a wide range of peptide antigens from diverse sources. HLA molecules and peptides present a complex molecular recognition pattern, as many peptides bind to a given allele and a given peptide can be recognized by many alleles. A powerful grouping scheme that not only provides an insightful classification, but is also capable of dissecting the physicochemical basis of recognition specificity is necessary to address this complexity. We present a hierarchical classification of 2010 class-I alleles by using a systematic divisive clustering method. All-pair distances of alleles were obtained by comparing binding pockets in the structural models. By varying the similarity thresholds, a multilevel classification was obtained, with 7 supergroups, each further subclassifying to yield 72 groups. An independent clustering performed based only on similarities in their epitope pools correlated highly with pocket-based clustering. Physicochemical feature combinations that best explain the basis of clustering are identified. Mutual information calculated for the set of peptide ligands enables identification of binding site residues contributing to peptide specificity. The grouping of HLA molecules achieved here will be useful for rational vaccine design, understanding disease susceptibilities and predicting risk of organ transplants.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the NATURE PUBLISHING GROUP, 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA
Department/Centre: Division of Biological Sciences > Biochemistry
Division of Physical & Mathematical Sciences > Mathematics
Date Deposited: 31 Jul 2015 14:47
Last Modified: 31 Jul 2015 14:47
URI: http://eprints.iisc.ac.in/id/eprint/51989

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