Diffusion Probabilistic Modeling of Protein Backbones in 3D for the Motif-Scaffolding problem

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.

Name thesis:degree_name

Master

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2023

Author dc:creator

• Yim, Jason

Advisors dc:contributor.advisor

• Jaakkola, Tommi S.
• Barzilay, Regina

Statement dc:rights

• In Copyright - Educational Use Permitted
• Copyright MIT

Licence dc:rights.uri

• http://rightsstatements.org/page/InC-EDU/1.0/

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/150230

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/150230