Generative modeling of intrinsically disordered protein regions by reinforcing sparse autoencoder features

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Original abstract

Intrinsically disordered protein regions (IDRs) play central roles in cellular processes such as transcriptional regulation, signal transduction, and subcellular localization, yet their functional design remains challenging. Structure-based design methods do not readily apply to IDRs, and existing protein language models are trained on full-length protein sequences, thus learning a prior that is biased towards folded domains. Here, we present IDiom, an autoregressive protein language model trained on IDiom-DB, a dataset of 54 million predicted IDRs curated from the AlphaFold Database. IDiom generates diverse sequences that recapitulate the composition, patterning, motifs, and predicted disorder of natural IDRs. To control function-associated sequence patterns, we also introduce reinforcement learning with sparse autoencoder features (RL-SAE), a post-training method that rewards the generation of sequences that activate specified feature sets. Across eight IDR design tasks, RL-SAE sequences activate, on average, 90% of 30 targeted features, compared to 24% for activation steering. We demonstrate that RL-SAE improves the predicted subcellular localization and transcriptional activity of generated IDRs compared to steering and supervised fine-tuning, and enables features associated with distinct biological functions to be combined within individual sequences. Thus, IDiom and RL-SAE enable interpretable and composable IDR design through explicit control of function-associated sequence features. More broadly, RL-SAE could extend to other protein design settings where interpretable features provide useful design targets. Code is available at https://github.com/rotskoff-group/idiom.

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