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. 2023 Dec 18;626(7998):435–442. doi: 10.1038/s41586-023-06953-1

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — a, Top: partial diffusion. RFdiffusion is used to denoise a randomly noised starting design (left); varying the extent of initial noising (middle row) enables control over the extent of introduced structural variation (bottom row; colours, new designs; grey, original design). Bottom left: partial diffusion diversifies designs. Note that the greater the amount of noise added, the more dissimilar the outputs are to the starting structure. Bottom right: depiction of the helix binder optimization strategy. b, Top: design model (spectrum) of the partially diffused binder to NPY (green) and FP measurements (n = 4) indicating a 5.3 nM binding affinity to NPY target and selectivity over PYY (brown). ND, not detectable. Bottom: design model (spectrum) of the partially diffused binder to GCG (yellow) and FP measurements (n = 4) indicating a subnanomolar binding affinity to GCG and selectivity over SCT (orange). c, Left: model (spectrum with GCG in grey) aligns with 0.72 Å RMSD to the 1.95-Å crystal structure (teal and yellow) of the RF_joint Inpainted GCG binder. Right: model (spectrum with GCG in grey) aligns with 0.6 Å RMSD to the 1.81-Å crystal structure (teal and yellow) of the partially diffused GCG binder. d, Left: the crystal structures of the Inpainted (grey) and partially diffused (teal and yellow) GCG binders have considerable topological similarity; there are many small readjustments. Right: FP titrations (n = 4) with GCG indicate much tighter binding following partial diffusion. e, Left inset: the crystal structure of the partially diffused backbone (teal) shows how the newly introduced Ile13 increases shape complementarity compared to the phenylalanine in the Inpainted binder (crystal structure in grey; structures aligned on residues 16–29 of GCG). Middle: crystal structure of the partially diffused GCG binder (teal and yellow). Right inset: the backbone shifts in the partially diffused structure (teal) enable Tyr16 to make packing and hydrogen-bonding interactions with the peptide; Ser16 in the original design did not make any peptide contacts (grey).