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In-Person Poster presentation / poster accept

Diffusion Probabilistic Modeling of Protein Backbones in 3D for the motif-scaffolding problem

Brian Trippe · Jason Yim · Doug Tischer · David Baker · Tamara Broderick · Regina Barzilay · Tommi Jaakkola

MH1-2-3-4 #111

Keywords: [ Machine Learning for Sciences ] [ geometric deep learning ] [ Diffusion Models ] [ sequential monte carlo ] [ protein design ]


Abstract:

Construction of a scaffold structure that supports a desired motif, conferring protein function, shows promise for the design of vaccines and enzymes. But a general solution to this motif-scaffolding problem remains open. Current machine-learning techniques for scaffold design are either limited to unrealistically small scaffolds (up to length 20) or struggle to produce multiple diverse scaffolds. We propose to learn a distribution over diverse and longer protein backbone structures via an E(3)-equivariant graph neural network. We develop SMCDiff to efficiently sample scaffolds from this distribution conditioned on a given motif; our algorithm is the first to theoretically guarantee conditional samples from a diffusion model in the large-compute limit. We evaluate our designed backbones by how well they align with AlphaFold2-predicted structures. We show that our method can (1) sample scaffolds up to 80 residues and (2) achieve structurally diverse scaffolds for a fixed motif.

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