BoltzGen: Toward Universal Binder Design

ABSTRACT We introduce BoltzGen, an all-atom generative model for designing proteins and peptides across all modalities to bind a wide range of biomolecular targets. BoltzGen builds strong structural reasoning capabilities about target-binder interactions into its generative design process. This is achieved by unifying design and structure prediction, resulting in a single model that also reaches state-of-the-art folding performance. BoltzGen’s generation process can be controlled with a flexible design specification language over covalent bonds, structure constraints, binding sites, and more. We experimentally validate these capabilities in a total of eight diverse wetlab design campaigns with functional and affinity readouts across 26 targets. The experiments span binder modalities from nanobodies to disulfide-bonded peptides and include targets ranging from disordered proteins to small molecules. For instance, we test 15 nanobody and protein binder designs against each of nine novel targets with low similarity to any protein with a known bound structure. For both binder modalities, this yields nanomolar binders for 66% of targets. We release model weights, data, and both inference and training code at: https://github.com/HannesStark/boltzgen.

Co-authors: Hannes Stark, Felix Faltings, MinGyu Choi, Yuxin Xie, Eunsu Hur, Timothy O’Donnell, Anton Bushuiev, Talip Uçar, Saro Passaro, Weian Mao, Mateo Reveiz, Roman Bushuiev, Tomáš Pluska, Josef Sivic, Karsten Kreis, Arash Vahdat, Shamayeeta Ray, Jonathan T. Goldstein, Andrew Savinov, Jacob A. Hambalek, Anshika Gupta, Diego A. Taquiri-Diaz, Yaotian Zhang, A. Katherine Hatstat, Angelika Arada, Nam Hyeong Kim, Ethel Tackie-Yarboi, Dylan Boselli, Lee Schnaider, Chang C. Liu, Gene-Wei Li, Denes Hnisz, David M. Sabatini, William F. DeGrado, Jeremy Wohlwend, Gabriele Corso, Regina Barzilay, Tommi Jaakkola