Improved motif-scaffolding with SE(3) flow matching

Abstract

Protein design often begins with the knowledge of a desired function from a motif which motif-scaffolding aims to construct a functional protein around. Recently, generative models have achieved breakthrough success in designing scaffolds for a range of motifs. However, generated scaffolds tend to lack structural diversity, which can hinder success in wet-lab validation. In this work, we extend FrameFlow, an SE(3) flow matching model for protein backbone generation, to perform motif-scaffolding with two complementary approaches. The first is motif amortization, in which FrameFlow is trained with the motif as input using a data augmentation strategy. The second is motif guidance, which performs scaffolding using an estimate of the conditional score from FrameFlow without additional training. On a benchmark of 24 biologically meaningful motifs, we show our method achieves 2.5 times more designable and unique motif-scaffolds compared to state-of-the-art. Code: https://github.com/microsoft/protein-frame-flow