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Ranking of binding and nonbinding peptides to MHC class I molecules using inverse folding approach: implications for vaccine design.

ABSTRACT: T cell recognition of the peptide-MHC complex initiates a cascade of immunological events necessary for immune responses. Accurate T-cell epitope prediction is an important part of the vaccine designing. Development of predictive algorithms based on sequence profile requires a very large number of experimental binding peptide data to major histocompatibility complex (MHC) molecules. Here we used inverse folding approach to study the peptide specificity of MHC Class-I molecule with the aim of obtaining a better differentiation between binding and nonbinding sequence. Overlapping peptides, spanning the entire protein sequence, are threaded through the backbone coordinates of a known peptide fold in the MHC groove, and their interaction energies are evaluated using statistical pairwise contact potentials. We used the Miyazawa & Jernigan and Betancourt & Thirumalai tables for pairwise contact potentials, and two distance criteria (Nearest atom >> 4.0 A & C-beta >> 7.0 A) for ranking the peptides in an ascending order according to their energy values, and in most cases, known antigenic peptides are highly ranked. The predictions from threading improved when used multiple templates and average scoring scheme. In general, when structural information about a protein-peptide complex is available, the current application of the threading approach can be used to screen a large library of peptides for selection of the best binders to the target protein. The proposed scheme may significantly reduce the number of peptides to be tested in wet laboratory for epitope based vaccine design.

SUBMITTER: Singh SP

PROVIDER: S-EPMC2639678 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Ranking of binding and nonbinding peptides to MHC class I molecules using inverse folding approach: implications for vaccine design.

Singh Satarudra Prakash SP Mishra Bhartendu Nath BN

Bioinformation 20081024 2

T cell recognition of the peptide-MHC complex initiates a cascade of immunological events necessary for immune responses. Accurate T-cell epitope prediction is an important part of the vaccine designing. Development of predictive algorithms based on sequence profile requires a very large number of experimental binding peptide data to major histocompatibility complex (MHC) molecules. Here we used inverse folding approach to study the peptide specificity of MHC Class-I molecule with the aim of obt ...[more]

PMID: 19238199

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Project description:BackgroundPeptides binding to Major Histocompatibility Complex (MHC) class II molecules are crucial for initiation and regulation of immune responses. Predicting peptides that bind to a specific MHC molecule plays an important role in determining potential candidates for vaccines. The binding groove in class II MHC is open at both ends, allowing peptides longer than 9-mer to bind. Finding the consensus motif facilitating the binding of peptides to a MHC class II molecule is difficult because of different lengths of binding peptides and varying location of 9-mer binding core. The level of difficulty increases when the molecule is promiscuous and binds to a large number of low affinity peptides. In this paper, we propose two approaches using multi-objective evolutionary algorithms (MOEA) for predicting peptides binding to MHC class II molecules. One uses the information from both binders and non-binders for self-discovery of motifs. The other, in addition, uses information from experimentally determined motifs for guided-discovery of motifs.ResultsThe proposed methods are intended for finding peptides binding to MHC class II I-Ag7 molecule - a promiscuous binder to a large number of low affinity peptides. Cross-validation results across experiments on two motifs derived for I-Ag7 datasets demonstrate better generalization abilities and accuracies of the present method over earlier approaches. Further, the proposed method was validated and compared on two publicly available benchmark datasets: (1) an ensemble of qualitative HLA-DRB1*0401 peptide data obtained from five different sources, and (2) quantitative peptide data obtained for sixteen different alleles comprising of three mouse alleles and thirteen HLA alleles. The proposed method outperformed earlier methods on most datasets, indicating that it is well suited for finding peptides binding to MHC class II molecules.ConclusionWe present two MOEA-based algorithms for finding motifs, one for self-discovery and the other for guided-discovery by experimentally determined motifs, and thereby predicting binding peptides to I-Ag7 molecule. Our experiments show that the proposed MOEA-based algorithms are better than earlier methods in predicting binding sites not only on I-Ag7 but also on most alleles of class II MHC benchmark datasets. This shows that our methods could be applicable to find binding motifs in a wide range of alleles.

Dataset Information

Ranking of binding and nonbinding peptides to MHC class I molecules using inverse folding approach: implications for vaccine design.

Publications

Ranking of binding and nonbinding peptides to MHC class I molecules using inverse folding approach: implications for vaccine design.

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