DeepInterAware: Deep Interaction Interface‐Aware Network for Improving Antigen‐Antibody Interaction Prediction from Sequence Data

Abstract Identifying interactions between candidate antibodies and target antigens is a key step in developing effective human therapeutics. The antigen–antibody interaction (AAI) occurs at the structural level, but the limited structure data poses a significant challenge. However, recent studies revealed that structural information can be learned from the vast amount of sequence data, indicating that the interaction prediction can benefit from the abundance of antigen and antibody sequences. In this study, DeepInterAware (deep interaction interface‐aware network) is proposed, a framework dynamically incorporating interaction interface information directly learned from sequence data, along with the inherent specificity information of the sequences. Experimental results in interaction prediction demonstrate that DeepInterAware outperforms existing methods and exhibits promising inductive capabilities for predicting interactions involving unseen antigens or antibodies, and transfer capabilities for similar tasks. More notably, DeepInterAware has unique advantages that existing methods lack. First, DeepInterAware can dive into the underlying mechanisms of AAIs, offering the ability to identify potential binding sites. Second, it is proficient in detecting mutations within antigens or antibodies, and can be extended for precise predictions of the binding free energy changes upon mutations. The HER2‐targeting antibody screening experiment further underscores DeepInterAware's exceptional capability in identifying binding antibodies for target antigens, establishing it as an important tool for antibody screening.