On the applicability domain of HADDOCK3 for protein-aptamer docking: documented failure modes from a 5x7 cross-target screening matrix and a 1676 aa receptor case study (P01031)

We screened a 5 receptor x 7 aptamer = 35-cell cross-target matrix with HADDOCK3 [1] under blind ambiguous-interaction-restraint (AIR) protocols on AlphaFold-modelled receptors. The screen surfaced 12 operationally distinct failure modes (collapsing to [~]8 conceptual classes; [§]3.1). The K_D-calibration subset is n = 4 cells with literature K_D records under matched assay conditions; the broader cohort includes [≥] 6 biological cognate or intended-cognate cells. The principal case study is P01031 (complement C5, 1676 aa, [≥] 12 structural domains): all 7 panel members produced positive HADDOCK3 top-1 scores under a scale-adaptive AIR. Score-term decomposition locates the anomaly in the AIR term (+217 to +268 to top-1 score). With AIR zeroed, scores fall to -131 to -74 -- the small-receptor regime. Boltz-2 cofolding chain-pair ipTM (cpi_AB) is an independent channel: P01031 shows the lowest median cpi_AB (0.211; 0/7 above the 0.5 confident-interface threshold). To our knowledge, this is the first reported case study of a 1676 aa multi-domain receptor exhibiting this signature under blind scale-adaptive AIR -- an n = 1 mechanistic case, not a statistical generalisation. We adapt the QSAR applicability domain concept [14-16] to in silico aptamer screening. [§]3.7 reports an empirical Mode 1 mitigation (pLDDT-aware AIR prefilter; cohort Jaccard recovery [~]10x).