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

Abstract

DNA methylation is a critical epigenetic modification that regulates gene expression and genome stability, primarily catalyzed by the DNA methyltransferase 3 (DNMT3) family of enzymes. Distinguishing precise sequence-specific flanking preferences between DNMT3A and DNMT3B remains computationally challenging due to the complex and high-dimensional nature of biochemical sequence data. In this study, we propose a novel Quantum Machine Learning (QML) approach to classify DNA methylation preferences, leveraging a Variational Quantum Classifier (VQC). Using experimentally derived deep enzymology data, we constructed a dataset containing 4,096 unique NNNCGNNN motifs. We evaluated a four-qubit VQC using a custom NumPy exact-statevector simulator. The described two-layer circuit contains 24 trainable rotations, eight CNOT gates, and eight input-encoding rotations, totaling 40 gates before measurement. Across five initialization seeds, the revised VQC evaluation achieved a ROC-AUC of 0.661 pm 0.009, where variability denotes sample standard deviation. The held-out test partition is approximately balanced, containing 200 DNMT3A-labeled motifs and 210 DNMT3B-labeled motifs. An always-DNMT3B predictor achieves 51.2% accuracy and a balanced accuracy of 0.500 on this test partition. This proof-of-concept establishes a foundation for utilizing near-term quantum architectures in complex epigenetic classification tasks, paving the way for hybrid quantum-classical pipelines in bioinformatics.