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bioRxiv · 10.64898/2026.06.23.733997

BoltzProt-1: Towards Efficient De Novo Binder Design with Good Developability

Ucar, T.·Bates, J.·Fu, Y.·Shi, W.·Stark, H.·Nava, D.·Cavalleri, L.·Wohlwend, J.·Corso, G.·Passaro, S.
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Abstract

Designing binders against novel protein targets remains a central challenge in computational drug discovery. Here we introduce BoltzProt-1, a pipeline for generating protein binders, including nanobodies, with improved hit rates and favorable developability properties. At its core lie a refined iteration of BoltzGens generative model and a novel protein-protein interaction prediction model, BoltzPPI. Employing BoltzPPI instead of BoltzGens standard structure-prediction confidence metrics to rank nanobody (VHH) designs increases the confirmed-binder hit rate from 3.3% to 8.0% across 10 novel targets. Assessed on 10 additional targets used in prior literature, the BoltzProt-1 pipeline obtains nanobody screening hits for 7 of 10 targets, surpassing the 6 of 10 previously reported by Chai-2. Finally, evaluating the developability of BoltzProt-1-designed nanobodies in terms of stability, aggregation, purity, polyspecificity and hydrophobicity reveals that 58% of its confirmed binders pass every criterion, exceeding both BoltzGen (40%) and clinical-stage VHH controls (21%). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/733997v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@d86de1org.highwire.dtl.DTLVardef@115da7eorg.highwire.dtl.DTLVardef@1bbb4e9org.highwire.dtl.DTLVardef@626a68_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Ucar, T., Bates, J., Fu, Y., Shi, W., Stark, H., Nava, D., Cavalleri, L., Wohlwend, J., Corso, G., Passaro, S.. 2026-06-27. BoltzProt-1: Towards Efficient De Novo Binder Design with Good Developability. https://doi.org/10.64898/2026.06.23.733997

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