On diffusion posterior sampling via sequential Monte Carlo for zero-shot scaffolding of protein motifs
File(s)
Published version
Author(s)
Young, Matthew
Akyildiz, O Deniz
Type
Journal Article
Abstract
With the advent of diffusion models, new proteins can be generated at an unprecedented rate. The motif scaffolding problem requires steering this generative process to yield proteins with a desirable functional substructure called a motif. While models have been trained to take the motif as conditional input, recent techniques in diffusion posterior sampling can be leveraged as zero-shot alternatives whose approximations can be corrected with sequential Monte Carlo (SMC) algorithms. In this work, we introduce a new set of guidance potentials for describing scaffolding tasks and solve them by adapting SMC-aided diffusion posterior samplers with an unconditional model, Genie, as a prior. In single motif problems, we find that (i) the proposed potentials perform comparably, if not better, than the conventional masking approach, (ii) samplers based on reconstruction guidance outperform their replacement method counterparts, and (iii) measurement tilted proposals and twisted targets improve performance substantially. Furthermore, as a demonstration, we provide solutions to two multi-motif problems by pairing reconstruction guidance with an SE(3)-invariant potential. We also produce designable internally symmetric monomers with a guidance potential for point symmetry constraints. Our code is available at: https://github.com/matsagad/mres-project.
Date Issued
2025-10-03
Date Acceptance
2025-09-15
Citation
Transactions of Machine Learning Research, 2025
ISSN
2835-8856
Publisher
OpenReview
Journal / Book Title
Transactions of Machine Learning Research
Copyright Statement
Copyright © 2025 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
License URL
Publication Status
Published online
Article Number
4502
Date Publish Online
2025-10-02