Abstract With the application of personalized and precision medicine, more precise and efficient antibody drug development technology is urgently needed. Identification of antibody-antigen interactions is crucial to antibody engineering. The time-consuming and expensive nature of wet-lab experiments calls for efficient computational methods. Taking into account the non-overlapping advantage of current structure-dependent and sequence-only computational methods, we propose an interpretable antibody-antigen interaction prediction method, S3AI. The introduction of structural knowledge, combined with explicit modeling of chemical rules, establishes a ‘sequence-to-function’ route in S3AI, thereby facilitating its perception of intricate molecular interactions through providing route and priors guidance. S3AI significantly and comprehensively outperforms the state-of-the-art models and exhibits excellent generalization when predicting unknown antibody-antigen pairs, surpassing specialized prediction methods designed for out-of-distribution generalization in fair comparisons. More importantly, S3AI captures the universal pattern of antibody-antigen interactions, which not only identifies the CDRs responsible for specific binding to the antigen but also unearths the importance of CDR-H3 for the interaction. Structure-free design and superior performance make S3AI ideal for large-scale, parallelized antibody optimization and screening, enabling the rapid and precise identification of promising candidates within the extensive antibody space.

Interpretable antibody-antigen interaction prediction by introducing route and priors guidance