On Diffusion Posterior Sampling via Sequential Monte Carlo for Zero-Shot Scaffolding of Protein Motifs

• Published in: arXiv.org 2024-12
• Main Authors: Young, James Matthew, Akyildiz, O Deniz
• Format: Article
• Language: English
• Subjects: Algorithms; Diffusion rate; Proteins; Reconstruction; Samplers; Sampling; Scaffolding; Steering; Symmetry
• ISSN: 2331-8422

With the advent of diffusion models, new proteins can be generated at an unprecedented rate. The \textit{motif scaffolding problem} requires steering this generative process to yield proteins with a desirable functional substructure -- 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 to describe and solve scaffolding tasks by adapting SMC-aided diffusion posterior samplers with an unconditional model, Genie, acting as a prior. Against established benchmarks, we successfully scaffold several single-motif and multi-motif problems. The latter is possible by pairing reconstruction guidance with \(\mathrm{SE}(3)\)-invariant potentials. In the single-motif case, we find these potentials perform comparably to the conventional masking approach and that reconstruction guidance outperforms replacement methods when aided with SMC. We additionally consider a guidance potential for point symmetry constraints and produce designable internally symmetric monomers with our setup. Overall, this work highlights the capabilities and areas for improvement of zero-shot posterior samplers in motif scaffolding tasks. Code is available at: https://github.com/matsagad/mres-project