Project: We benchmarked whether Boltz-2 (an AlphaFold-class structure predictor) can substitute for a binding measurement, testing two complementary questions across two systems: does its confidence score rank affinity (SH2 domains vs. measured KD panels for c-Src and Fyn), and does it detect a damaged interface (MDM2:PMI under site-saturation mutagenesis). What we found: Boltz-2 reliably separates binders from non-binders — free two-peptide competition is the best readout (65% c-Src, 81% Fyn) — and maps which residues matter with anchor-localized, chemically-coherent sensitivity. But it cannot resolve fine affinity rank among true binders (the Fyn 1-log test collapses, residual pointing the wrong way), and the peptide-linker fusion trick does not transfer to a folded protein–protein interface (barnase–barstar fails at every linker length, even femtomolar wild-type). Why it matters: It draws a clear, evidence-backed boundary for using structure-prediction confidence as an affinity proxy — sound for binder/non-binder triage and interface-hotspot reading, unreliable for quantitative ranking — so users know which question the score can actually answer before they trust it.
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