From Atoms to Fragments: A Coarse Representation for Functional and Efficient Protein Design

Abstract

MotivationAlthough 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 [Formula] of the dimensions required by traditional methods. ResultsOn 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 [~]68.7x faster than RMSD-based structural methods and [~]1.64x 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. Availabilityhttps://github.com/wells-wood-research/tessera (Documentation to be made available upon acceptance)