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 **I**mplicit **S**equence **M**odel, a sequence-only input model with structurally-enriched representations that outperforms state-of-the-art sequence models 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.

We present Ambient Protein Diffusion, a framework for training protein diffusion models that generates structures with unprecedented diversity and quality. State-of-the-art generative models are trained on computationally derived structures from AlphaFold2 (AF), as experimentally determined structures are relatively scarce. The resulting models are therefore limited by the quality of synthetic datasets. Since the accuracy of AF predictions degrades with increasing protein length and complexity, de novo generation of long, complex proteins remains challenging. Ambient Protein Diffusion overcomes this problem by treating low-confidence AF structures as corrupted data. Rather than simply filtering out low-quality AF structures, our method adjusts the diffusion objective for each structure based on its corruption level, allowing the model to learn from both high and low quality structures. Empirically, ambient protein diffusion yields major improvements: on proteins with 700 residues, diversity increases from 45% to 85% from the previous state-of-the-art, and designability improves from 70% to 88%.

Stabilizing proteins is a foundational step in protein engineering. However, the evolutionary pressure of all extant proteins makes identifying the scarce number of mutations that will improve thermodynamic stability challenging. Deep learning has recently emerged as a powerful tool for identifying promising mutations. Existing approaches, however, are computationally expensive, as the number of model inferences scales with the number of mutations queried. Our main contribution is a simple, parallel decoding algorithm. Mutate Everything is capable of predicting the effect of all single and double mutations in one forward pass. It is even versatile enough to predict higher-order mutations with minimal computational overhead. We build Mutate Everything on top of ESM2 and AlphaFold, neither of which were trained to predict thermodynamic stability. We trained on the Mega-Scale cDNA proteolysis dataset and achieved state-of-the-art performance on single and higher-order mutations on S669, ProTherm, and ProteinGym datasets. Our code is available at https://github.com/jozhang97/MutateEverything.