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Diffusion probabilistic modeling of protein backbones in 3D for the motif-scaffolding problem
Jason Yim · Brian L Trippe · Doug Tischer · David Baker · Tamara Broderick · Regina Barzilay · Tommi Jaakkola

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in Machine Learning in Structural Biology Workshop »

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 ProtDiff 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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Author Information

Jason Yim (MIT)
Brian L Trippe (Columbia University)
Doug Tischer (University of Washington)
David Baker (University of Washington)
Tamara Broderick (MIT)
Regina Barzilay (Massachusetts Institute of Technology)
Tommi Jaakkola (MIT)

Tommi Jaakkola is a professor of Electrical Engineering and Computer Science at MIT. He received an M.Sc. degree in theoretical physics from Helsinki University of Technology, and Ph.D. from MIT in computational neuroscience. Following a Sloan postdoctoral fellowship in computational molecular biology, he joined the MIT faculty in 1998. His research interests include statistical inference, graphical models, and large scale modern estimation problems with predominantly incomplete data.

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