Co-DIRECT: Adaptive Coordination of Sequence and Structure for Protein Design

Joint generative models aim to produce compatible outputs by allowing their predictions to inform one another. In protein design, this requires coordinating an amino-acid sequence with its three-dimensional structure. Yet stronger influence between these predictions does not necessarily make that influence beneficial. We investigate this distinction in a joint protein generator and find that the benefit of an additional prediction varies across residues and tasks, while the resulting response can increase reference-based prediction error. We introduce Co-DIRECT to adaptively coordinate sequence and structure through two components: anticipation and a router. Anticipation probes how the model's predictions respond to a tentative update, providing corrections that account for the coupled response. The router uses information from both sequence and structure representations to determine which representation receives these corrections at each residue. Together, these components regulate generation without querying an external structure predictor during sampling. Across binder design, enzyme scaffolding, and antibody CDR redesign, Co-DIRECT improves the reported mean assessments of refolded designs relative to frozen and fully adapted Proteina-Complexa. Component ablations and routing controls support the combined approach, with improved outcomes accompanied by fewer local error-increasing responses. These findings support adaptive coordination of sequence and structure as a strategy for improving joint protein generation.