From atoms to fragments: a coarse representation for efficient and functional protein design.

Abstract

Although deep learning has accelerated protein design, current protein representations such as sequences or full-atom structures scale non-linearly with protein length. We propose a sparse and interpretable representation for proteins, based on evolutionarily conserved fragments. Specifically, we use a curated set of 40 functional and evolutionarily conserved fragments as an alphabet to build Fragment Graphs and Fragment Sets. These fragment-based representations are both lightweight and functionally informative, capturing up to 55% more variance using fewer than 13 of the dimensions required by traditional methods. On a dataset of 215 functionally diverse proteins, our approach creates more coherent functional clusters than traditional sequence- and structure-based methods, even among proteins with ≤30% sequence identity. Fragment-based searches of protein databases achieve accuracies comparable to traditional methods, while using 90% fewer tokens per protein. These searches execute ∼68.7× faster than RMSD-based structural methods and ∼1.64× faster than sequence-based methods, even including fragment pre-processing overhead. Additionally, we show that our representation effectively guides RFDiffusion for protein backbone generation with functional recovery rates higher than 40%. In summary, our fragment-based representation offers a scalable and interpretable alternative for the next generation of protein design tools for backbone design, sequence design, and functional similarity searches within protein structure databases. https://github.com/wells-wood-research/tessera.