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.

Rosetta is one of the leading algorithms for protein structure prediction today. It is a Monte Carlo energy minimization method requiring many random restarts to find structures with low energy. In this paper we present a resampling technique for structure prediction of small alpha/beta proteins using Rosetta. From an initial roundof Rosetta sampling, we learn properties of the energy landscape that guide a subsequent round of sampling toward lower-energy structures. Rather than attempt to fit the full energy landscape, we use feature selection methods--both L1-regularized linear regression and decision trees--to identify structural features that give rise to low energy. We then enrich these structural features in the second sampling round. Results are presented across a benchmark set of nine small alpha/beta proteinsdemonstrating that our methods seldom impair, and frequently improve, Rosetta's performance.