Distilling Structural Representations into Protein Sequence Models

Protein language (or sequence) models, like the popular ESM2, are now widely used tools for extracting evolution-based protein representations and have achieved significant success on core downstream biological tasks. A major open problem is how to obtain representations that best capture both the sequence evolutionary history and the atomic structural properties of proteins in general. We introduce Implicit Sequence Model, a sequence-only input model with structurally-enriched representations that outperforms state-of-the-art methods on several well-studied benchmarks including mutation stability assessment and structure prediction. Our key innovations are a microenvironment-based Autoencoder for generating structure tokens and a self-supervised training objective that distills these tokens into ESM2's pre-trained model. Notably, we make ISM's structure-enriched weights easily accessible for any application using the ESM2 framework.