Interpretable enzyme function prediction via sparse autoencoder features of ESMC across the microbial protein universe

Microbial genomes and metagenomes contain millions of proteins whose enzymatic functions remain unknown, the enzyme dark matter. The new analysis still awaits peer review, but it already lays out the central claim clearly.

It matters because cosmology operates at the edge of what current instruments can measure, where systematic errors and model assumptions are never trivial. Small discrepancies between independent measurements have historically pointed toward missing physics rather than simple calibration errors, and the ongoing tension in the Hubble constant is a live example of how a persistent disagreement between methods can reshape the theoretical landscape. Each new dataset that approaches this territory with independent systematics adds real information to a problem that has resisted easy resolution for more than a decade. While deep learning has improved protein function prediction, most methods are black boxes relying on sequence or structural similarity, limiting discovery of novel catalytic. The ESMC-6B protein language model and its sparse autoencoder with a 16, 384-dimensional codebook of interpretable biological concepts, each annotated by GPT-5, creates a new.

Here, we show that ESMC-SAE features enable accurate and interpretable enzyme commission (EC) number prediction without task-specific training or GPU-intensive computation. On a balanced benchmark of 4, 868 microbial SwissProt enzymes across 161 EC3 subclasses, ESMC-SAE binary features achieve 78.9% top-1 and 88.5% top-5 accuracy, 37.

In leave-one-EC3-class-out evaluation simulating discovery of novel enzyme classes, SAE features recover the EC1 superclass in 47.7% of cases (3.3x random, 14.3%), versus 26. Discriminative features correspond to mechanistically interpretable concepts: catalytic triad geometry for hydrolases, NAD(P)H-binding Rossmann folds for oxidoreductases.

We also survey the ESM Atlas of 7.7 million clusters and identify 169, 859 dark enzyme-like candidates across all major microbial phyla. Our results establish a paradigm for enzyme function discovery in microbial dark matter: interpretable by design, scalable without GPU clusters, and applicable to the billions of.

The relevance goes beyond one dataset because even small shifts in measured parameters can matter when the field is testing the limits of the standard cosmological model. The Lambda-CDM framework describes the observable universe with remarkable economy, but its success rests on two components, dark matter and dark energy, whose physical nature remains entirely unknown. Any credible measurement that tightens or loosens the constraints on those components moves the entire theoretical enterprise forward, regardless of whether the immediate result looks dramatic on its own terms.

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Because this is still a preprint, the result should be read with genuine interest and proportionate caution. Peer review is not a guarantee of correctness, but it is a process that forces authors to respond to technical criticism from specialists who have no stake in a particular outcome. Preprints that survive that process, often with substantive revisions, emerge with a stronger evidential base than the version that first appeared. Until that stage is complete, the responsible reading keeps uncertainty explicitly visible rather than treating the claims as established findings.

The next step is to see whether the effect survives when independent surveys, different calibration strategies and tighter control of systematic uncertainties enter the picture. Programmes such as Euclid, DESI and the Rubin Observatory will deliver datasets over the next several years that cover the same parameter space with largely independent methods. If the current signal persists through those tests, its theoretical implications will become impossible to set aside. Until peer review and independent follow-up address those open questions, skepticism is not a failure of appreciation for the work; it is part of how science decides what to keep.

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