Harnessing Fuzzy Rule Based System for Screening Major Histocompatibility Complex Class I Peptide Epitopes from the Whole Proteome: An Implementation on the Proteome of Leishmania donovani.

Abstract

The development of peptide-based vaccines is enhanced by immunoinformatics, which predicts the patterns that B cells and T cells recognize. Although several tools are available for predicting the Major histocompatibility complex (MHC-I) binding peptides, the wide variants of human leucocyte antigen allele make it challenging to choose a peptide that will induce an immune response in a majority of people. In addition, for a peptide to be considered a potential vaccine candidate, factors such as T cell affinity, proteasome cleavage, and similarity to human proteins also play a major role. Identifying peptides that satisfy the earlier cited measures across the entire proteome is, therefore, challenging. Hence, the fuzzy inference system (FIS) is proposed to detect each peptide's potential as a vaccine candidate and assign it either a very high, high, moderate, or low ranking. The FIS includes input features from 6 modules (binding of 27 major alleles, T cell propensity, pro-inflammatory response, proteasome cleavage, transporter associated with antigen processing, and similarity with human peptide) and rules derived from an observation of features on positive samples. On validation of experimentally verified peptides, a balanced accuracy of ∼80% was achieved, with a Mathew's correlation coefficient score of 0.67 and an F-1 score of 0.74. In addition, the method was implemented on complete proteome of Leishmania donovani, which contains ∼4,800,000 peptides. Lastly, a searchable database of the ranked results of the L. donovani proteome was made and is available online (MHC-FIS-LdDB). It is hoped that this method will simplify the identification of potential MHC-I binding candidates from a large proteome.