Structure-Aware Masking for Protein Representation Learning
Authors: Thomas Walton, Ayan Goel, Amirali Aghazadeh
Organizations: Georgia Institute of Technology
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.
Antibody-specific language models pretrained via masked language modeling (MLM) learn representations that are critical for downstream sequence design and property prediction tasks. Yet, the corruption process itself is rarely leveraged as a source of inductive bias during pretraining. While preferentially masking complementarity-determining regions (CDRs) improves binding-related predictions, antibodies possess diverse biological priors over a variety of functions. Herein, we introduce function-aware masking, a family of pretraining algorithms that align mask placement with specific functional priors (e.g., from IMGT annotations or structure predictions) to shape the learned representation space. We show that these specialist masking strategies significantly improve performance on their respective objectives, yielding up to a 14% gain on structure-related tasks and up to a 5.9x improvement on CDR-related tasks. To further improve performance across multiple functional axes, we develop hybrid masking strategies that integrate multiple priors, balancing reconstruction over binding, structural, and biophysical objectives. Our results demonstrate that informed mask placement provides a parameter-free mechanism for imposing functional inductive biases in antibody language model training.
Protein language models are trained primarily with masked language modeling (MLM), which predicts amino-acid identities at masked positions. We ask whether latent-space prediction can complement these token-level objectives under matched wall-clock budget. Across pretrained and random-init protein sequence encoders at 35--150M parameters, we find that the best protein-JEPA design is not all-position latent prediction but a variant: predicting latent targets only at masked positions, and retaining the MLM cross-entropy. We call this recipe masked-position MLM+JEPA. On a 16-task downstream suite (15 frozen linear probes plus SCOPe-40 zero-shot fold retrieval), under matched wall-clock budgets, this recipe wins more tasks than it loses against MLM-only continuation: 10 wins / 3 losses / 3 ties (hereafter W/L/T) on pretrained ESM2-35M, 11/2/3 on ESM2-150M while results in pretraining from scratch are mixed (6/8/2). Gains are seen for multiple models on 11 of 16 tasks, including stability, \b{eta}β\b{eta}-lactamase fitness, variant effect, intrinsic disorder, remote homology, enzyme classification, and SCOPe-40 fold retrieval. Tasks with more losses than wins are Fluorescence (TAPE) and Peptide-HLA Binding. All-position MLM+JEPA matches MLM-only overall but does not reproduce the masked-position gains. JEPA-only (no MLM) collapses in nearly every experiment. We conclude that JEPA, when combined with MLM, is competitive and can outperform pure MLM in pretraining and continued training, even under matched wall-clock budgets.
Proteins perform diverse cellular functions, and even single amino-acid substitutions can alter stability, activity, or molecular interactions. Protein language models (PLMs) provide a scalable approach for modeling such sequence--function relationships from unlabeled sequences, but increasing the size of dense Transformer backbones often brings substantial computational cost without consistently improving mutation-sensitive prediction. We introduce ProtLingo, an efficient PLM framework that augments a pretrained single-sequence backbone with conditional local memory and sparse expert routing. ProtLingo maps contextual residue representations into route-specific discrete codes, composes centered local windows into latent N-gram addresses, and retrieves reusable residual signals associated with recurring local sequence contexts. In parallel, selected feed-forward blocks are upcycled into sparse Mixture-of-Experts layers with shared and routed experts, enabling residue-dependent computation while activating only a subset of parameters. Experiments on protein fitness prediction, FLIP benchmarks, and supervised contact prediction show that ProtLingo achieves competitive performance with a 150M-scale backbone, including strong parameter efficiency on mutation-effect prediction and preserved long-range structural representations.