Abstract
Proteins typically interact with multiple partners to regulate biological processes, and peptide drugs targeting multiple receptors have shown strong therapeutic potential, emphasizing the need for multi-target strategies in protein design. However, most current protein sequence design methods focus on interactions with a single receptor, often neglecting the complexity of designing proteins that can bind to two distinct receptors. We introduced Protein Dual-Target Design Network (ProDualNet), a structure-based sequence design method that integrates sequence-structure information from two receptors to design dual-target protein sequences. ProDualNet used a heterogeneous graph network for pretraining and combines noise-augmented single-target data with real dual-target data for fine-tuning. This approach addressed the challenge of limited dual-target protein experimental structures. The efficacy of ProDualNet has been validated across multiple test sets, demonstrating better recovery and success rates compared to other multi-state design methods. In silico evaluation of cases like dual-target allosteric binding and non-overlapping interface binding highlights its potential for designing dual-target binding proteins. Data and code are available at https://github.com/chengliu97/ProDualNet.