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bioRxiv · 10.64898/2026.10.04.753929

Benchmarking interface confidence as a selection criterion for computational nanobody design against survivin's BIR-domain groove

Gately, C.·Guan, X.·Ding, X.
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Abstract

Designed binders are routinely filtered on predicted interface confidence, which reports how self-consistently a model places an interface, not where it lies. We designed 200 nanobody loops against the survivin BIR-domain groove, co-folded 196, and checked epitope contact in every predicted complex. Confidence showed no detectable association with epitope engagement ({rho} = +0.100, 95% CI -0.04 to +0.24, n = 196); its highest and lowest quartiles failed alike (odds ratio 0.97, 95% CI 0.41 to 2.26). It tracked instead the run's other confidence estimates ({rho} = +0.61). Twelve-seed replication separated two candidates the criteria had not: one reached the complete epitope in 10 of 12 runs, the other never. Across 155 predictions the top-ranked model was no better than one drawn at random from its five (P = 0.610), though only 3 of 31 failed on every model. Nothing was assayed; nb_cand_057 is an in silico candidate only.

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Gately, C., Guan, X., Ding, X.. 2026-10-11. Benchmarking interface confidence as a selection criterion for computational nanobody design against survivin's BIR-domain groove. https://doi.org/10.64898/2026.10.04.753929

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