A systematic evaluation framework for universal antibody-antigen binding affinity prediction and candidate recommendation

Abstract

Summary Predicting antigen-antibody binding is essential to drug discovery and protein engineering. For de novo antibody design, generalizable binding prediction models are crucial for efficient in silico screening. However, existing affinity predictors lack generalization, with performance deteriorating for antibodies targeting antigens absent from training data or datasets lacking non-binders. To address this, we establish a benchmarking framework for evaluating universal antibody-antigen binding affinity prediction. Our framework compares sequence- and structure-based methods across diverse antigens, introducing standardized evaluation protocols based on pairwise accuracy and retrieval metrics. We propose MochiBind, a sequence-only pairwise binding affinity predictor, and benchmark it against structure-derived baselines such as Boltz-2, GeoDock, and Graphinity. The results show that MochiBind achieves comparable or superior performance in pairwise accuracy and retrieval, suggesting that sequence-based approaches can match or surpass structure-based models in generalization. The proposed benchmark provides a foundation for fair comparison and future development, enabling scalable, sequence-driven solutions to binding affinity prediction.