TrustCDR: Reliability-Guided CDR Co-Design under Local Antigen Uncertainty

Target-specific antibody CDR sequence–structure design uses antigen geometry to guide binding-interface generation. Recent antigen-aware generators encode this geometry but generally do not estimate its local reliability and may therefore assign comparable trust to geometrically heterogeneous cues. Antigen structures used for design may be experimentally reconstructed, predicted, docked, or preprocessed and may also contain conformationally variable regions. Such structures can be globally plausible while their local geometric cues differ in reliability. Consequently, lower-reliability cues may exert excessive influence on CDR–antigen relation updates and degrade interface quality. We introduce TrustCDR, which estimates a reference-free, perturbation-based relative geometric reliability signal and converts it into relative trust weights that modulate residual CDR–antigen pair updates. Starting from a single observed antigen, TrustCDR constructs a reference-free perturbation ensemble and evaluates residue-level stability across coordinate, topology, orientation, and surface cues. It preserves the base antigen condition and uses down-only raw weights with mean-preserving normalization to reduce the relative influence of lower-reliability regions. On the RAbD test set, TrustCDR achieves 68.52% AAR, 0.57 RMSD, and 0.76 DockQ under clean inputs, while maintaining 0.75 DockQ under a 1.5 epitope perturbation. It also achieves IMP rates of 18.50% and 20.40% under clean and epitope-perturbed inputs, respectively.