CONTRA-IL6: an interpretable hybrid convolutional neural network and Transformer framework for accurate prediction of interleukin-6-inducing peptides using protein language models.

Abstract

Interleukin-6 (IL-6) is a key immunomodulatory cytokine implicated in diverse physiological processes and pathological conditions, including autoimmune diseases, cancers, and cytokine storms. Immunogenic peptides capable of inducing IL-6 expression are key modulators of host immune responses and represent promising candidates for therapeutic design and epitope-based vaccine development. However, experimental identification of IL-6-inducing peptides remains laborious and unsuitable for large-scale screening. Although existing computational approaches show promise, many often struggle to capture both global contextual semantics and local motif-level features essential for peptide immunogenicity. To address these limitations, we present CONTRA-IL6, a novel deep learning framework that integrates Transformer fusion and convolutional localization modules with stacked pretrained protein language model embeddings to predict IL-6-inducing peptides. Comprehensive benchmarking on an independent dataset demonstrates that CONTRA-IL6 achieves superior predictive performance over six state-of-the-art predictors. Notably, it achieves the highest Matthews correlation coefficient (MCC, 0.504) and F1 (0.549) and improves over the best-performing existing method by 3.2% in MCC and 4.3% in F1, demonstrating balanced and robust performance. Feature space visualizations (uniform manifold approximation and projection, kernel density estimation) showed clear class separation, while 1D gradient-weighted class activation mapping++ highlighted strong attention to specific C-terminal regions. Crucially, we moved beyond these attribution methods by employing in silico mutagenesis, which causally confirmed the functional importance and physicochemical constraints. Ablation studies further confirmed the synergistic contribution of global and local modules to model performance. CONTRA-IL6 offers a robust, scalable, and interpretable solution for immunoinformatics research. The standalone package is freely available at https://pypi.org/project/contra-il6/ to facilitate broader community use.