Structure-Aware Masking for Protein Representation Learning

Abstract:Masked language modeling (MLM) is the standard objective for training protein language models, typically implemented by randomly masking individual residues at a fixed rate (e.g., 15%). This practice implicitly assumes that all sequence positions contribute equally to representation learning. In downstream fitness prediction tasks, however, protein sequences are governed by three-dimensional structural dependencies and long-range residue contacts that induce strong nonlocal couplings between residues. We introduce Bucket Masking, a structure-aware masking strategy that selects groups of residues based on their proximity in three-dimensional space, preferentially masking structurally coupled regions during training. By conditioning the masking distribution on residue contacts, Bucket Masking shifts the learning objective toward modeling long-range interactions that are critical for protein function. Across four downstream protein fitness prediction tasks, Bucket Masking enables up to a 14% improvement over standard random masking, excelling at predicting higher-order mutational interactions. Through controlled ablations, we show that these improvements arise from mask placement rather than span size, establishing masking as a positional inductive bias.

Machine Learning (cs.LG)

arXiv:2605.16581 [cs.LG]

(or arXiv:2605.16581v2 [cs.LG] for this version)

https://doi.org/10.48550/arXiv.2605.16581 Focus to learn more arXiv-issued DOI via DataCite

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