AbLWR: A Context-Aware Listwise Ranking Framework for Antibody-Antigen Binding Affinity Prediction via Positive-Unlabeled Learning
Fan Xu, Zhi-An Huang, Haohuai He, Yidong Song, Wei Liu, Dongxu Zhang, Yao Hu, Jibin Wu, Kay Chen TanAbstract
Motivation
Accurate prediction of antibody-antigen binding affinity is fundamental to therapeutic design and the rapid response to evolving pathogens. However, current computational approaches predominantly formulate this as a point-wise regression task. This paradigm struggles to discriminate subtle affinity differences among highly homologous variants and lacks the global context necessary to effectively prioritize top-tier candidates. Furthermore, the field is severely constrained by label sparsity. Although sequence data is abundant, experimentally verified affinities are scarce, leaving a massive pool of unverified antibody-antigen structural interactions unexploited by standard supervised paradigms.
Results
We propose AbLWR (Antibody-antigen binding affinity Listwise Ranking), a novel framework that reformulates the conventional affinity regression task as a listwise ranking problem to directly optimize candidate prioritization. To mitigate label sparsity, AbLWR incorporates a Positive-Unlabeled (PU) learning mechanism, leveraging a dual-level contrastive objective and meta-optimized label refinement to distill robust structural representations from vast unlabeled data. To accommodate antigenic variation, we employ a homologous antigen sampling strategy coupled with a Multi-Head Self-Attention (MHSA) module, which explicitly models inter-sample dependencies within training lists to capture subtle affinity nuances. Extensive evaluations demonstrate that AbLWR significantly outperforms state-of-the-art sequence-, structure-, and complex-based baselines. It improves the Full Rank Accuracy (FRA) by approximately 8% compared to the strongest baseline in randomized cross-validation, and exhibits strong robustness in out-of-distribution scenarios involving distinct antigen and antibody clusters. Case studies on Influenza Viruses and Human Interleukin-33 further validate its practical utility. Specifically, AbLWR successfully tracks affinity drops caused by antigenic drift and immediately captures optimal binders in simulated wet-lab screening.
Availability
Source code and datasets are freely available at https://github.com/Josie-xufan/AbLWR.
Supplementary information
Supplementary data are available at Bioinformatics online.