A 4-Qubit Variational Quantum Classifier for Sequence-Specific Classification of DNMT3A and DNMT3B Flanking Methylation Preferences

Accurate computational identification of DNA methylation is essential for understanding epigenetic regulation. Although deep learning excels in this binary classification task, its "black-box" nature impedes biological insight. We address this by introducing a high-performance model MEDNA-DFM, alongside mechanism-inspired signal purification algorithms. Our investigation demonstrates that MEDNA-DFM effectively captures conserved methylation patterns, achieving robust distinction across diverse species. Validation on external independent datasets confirms that the model's generalization is driven by conserved intrinsic motifs (e.g., GC content) rather than phylogenetic proximity. Furthermore, applying our developed algorithms extracted motifs with significantly higher reliability than prior studies. Finally, empirical evidence from a Drosophila 6mA case study prompted us to propose a "sequence-structure synergy" hypothesis, suggesting that the GAGG core motif and an upstream A-tract element function cooperatively. We further validated this hypothesis via in silico mutagenesis, confirming that the ablation of either or both elements significantly degrades the model's recognition capabilities. This work provides a powerful tool for methylation prediction and demonstrates how explainable deep learning can drive both methodological innovation and the generation of biological hypotheses.

DNA sequence classification requires not only high predictive accuracy but also the ability to uncover latent site interactions, combinatorial regulation, and epistasis-like higher-order dependencies. Although the standard Transformer provides strong global modeling capacity, its softmax attention is continuous, dense, and weakly constrained, making it better suited for information routing than explicit structure discovery. In this paper, we propose a Boltzmann-machine-enhanced Transformer for DNA sequence classification. Built on multi-head attention, the model introduces structured binary gating variables to represent latent query-key connections and constrains them with a Boltzmann-style energy function. Query-key similarity defines local bias terms, learnable pairwise interactions capture synergy and competition between edges, and latent hidden units model higher-order combinatorial dependencies. Since exact posterior inference over discrete gating graphs is intractable, we use mean-field variational inference to estimate edge activation probabilities and combine it with Gumbel-Softmax to progressively compress continuous probabilities into near-discrete gates while preserving end-to-end differentiability. During training, we jointly optimize classification and energy losses, encouraging the model to achieve accurate prediction while favoring low-energy, stable, and interpretable structures. We further derive the framework from the energy function and variational free energy to the mean-field fixed-point equations, Gumbel-Softmax relaxation, and the final joint objective. The proposed framework provides a unified view of integrating Boltzmann machines, differentiable discrete optimization, and Transformers for structured learning on biological sequences.

GBM is a highly aggressive primary malignancy in adults, necessitating personalized therapeutic strategies due to its inherent molecular heterogeneity. MGMT promoter methylation is a pivotal prognostic biomarker for anticipating response to temozolomide-based chemotherapy. Although various AI frameworks have been developed for non-invasive MGMT prediction, spatial heterogeneity of methylation status and the high-dimensional and correlated nature of MRI data frequently constrain discriminative feature learning and generalizability of classical models. To circumvent these limitations, a specialized IA-QCNN architecture is proposed, based on the principles of quantum mechanics, including superposition and entanglement, and enabling more efficient representation learning in high-dimensional Hilbert space. The framework establishes a methodological bridge between GBM radiogenomics and quantum deep learning by integrating energy-based slice selection, importance-aware weighting, ring-topology quantum convolution, and folding-based pooling layers. When the model predicts MGMT promoter methylation status using both mpMRI and T1Gd images, experimental results demonstrate that the IA-QCNN achieves high accuracy despite its low number of trainable parameters while effectively minimizing the overfitting problem observed in classical models. Quantitative analyses reveal that the T1Gd modality possesses higher discriminative power than mpMRI, establishing a clinically significant sequence preference. Furthermore, the model exhibits exceptional robustness in hybrid noise environments, effectively utilizing noise as a regularization mechanism to enhance predictive performance. Consequently, the specialized IA-QCNN architecture provides a robust and computationally efficient alternative to classical approaches in the analysis of heterogeneous radiogenomic data.