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bioRxiv · 10.64898/2026.05.11.724439

MuseDrift: Navigating Protein Evolutionary Manifolds with Conditional Discrete Diffusion

Wang, C.·Wang, Y.
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Abstract

Protein engineering often requires generating variants of a wild-type (WT) sequence while controlling how far they drift in sequence space. Existing generative models support de novo design but offer limited control over WT similarity. We introduce MO_SCPLOWUSEC_SCPLOWDO_SCPLOWRIFTC_SCPLOW, a conditional discrete diffusion model for WT-anchored, distance-controlled protein generation. Trained on a 38.2M-pair Seed-and-Stratify corpus, MO_SCPLOWUSEC_SCPLOWDO_SCPLOWRIFTC_SCPLOW combines WT-prefix conditioning with random-order iterative unmasking to enable stable multi-residue generation. Its key feature is a calibrated identity dial: after lightweight calibration, generated sequences match a target WT identity{tau} within approximately {+/-}0.05 over{tau} [isin] [0.55, 0.95] on held-out probes. On Mol-Instructions and CAMEO under shared evaluation oracles, MO_SCPLOWUSEC_SCPLOWDO_SCPLOWRIFTC_SCPLOW is competitive with multimodal and text-conditioned baselines while uniquely providing explicit identity control. At{tau} = 0.95, it achieves pLDDT scores of 84.97 on Mol-Instructions and 83.14 on CAMEO with only 85M parameters, rivaling much larger 1.8B-2B models. Evolutionary and FO_SCPLOWOLDC_SCPLOWX analyses further support biological plausibility and structural stability.

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Wang, C., Wang, Y.. 2026-05-12. MuseDrift: Navigating Protein Evolutionary Manifolds with Conditional Discrete Diffusion. https://doi.org/10.64898/2026.05.11.724439

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