MDLAS: Multi-Dimension Leakage-Aware Splits for Antibody-Antigen Structural Benchmarks

Existing antibody-antigen structural benchmarks often treat leakage control primarily as a sequence-level property. We argue that this is insufficient: a split can prevent direct sequence overlap while retaining redundancy through shared antigens, epitopes, or paired antibody sequences, and can still exhibit substantial distributional imbalance. We present MDLAS (Multi-Dimension Leakage-Aware Split), a framework for constructing antibody-antigen structural benchmark splits that jointly controls cross-split redundancy and marginal distributional consistency. MDLAS builds a multi-relation graph over five redundancy signals spanning CDR-H3 identity (exact duplication and sequence clustering), antigen identity (shared antigen chains), epitope identity (shared binding footprint), and paired variable-domain similarity (co-occurring heavy/light chain pairs), assigns connected components indivisibly across train, validation, and test, and then optimizes the remaining feasible assignments across seven metadata axes. On a 15,557-entry protein/peptide-antigen working population, MDLAS produces an 80/10/10 split (12,445/1,556/1,556 entries) at the primary 70% CDR-H3 identity tier; independent auditing confirms zero cross-split overlap for the modeled redundancy relations, while distributional consistency is measured directly from the resulting assignments. This leakage control involves a substantial trade-off: because component assignment is indivisible, an antigen-dominated component containing 8,029 entries (51.6% of the working population) would overwhelm the balance of whichever split received it. Together with low-resolution-only components, it therefore cannot be assigned to the validation or test split. We further evaluate four CDR-H3 design baselines (MEAN, DiffAb, RefineGNN, and AgForce) under MDLAS. The models exhibit distinct performance profiles, and a binding-accuracy ranking reported on a smaller, differently constructed benchmark does not transfer to MDLAS, demonstrating that relative model comparisons can depend on benchmark construction. These results motivate treating leakage structure, distributional composition, and residual within-test redundancy as distinct properties when designing antibody structural benchmarks.