Reverse Distillation: Consistently Scaling Protein Language Model Representations

Protein language models (PLMs) have transferred the latest advances from natural language processing to computational biology. These models, trained on large corpora of protein sequence data, are widely used to translate amino acid sequences into latent-space embeddings, ready for use in diverse downstream tasks (DTs). By consensus, embeddings from the models' last layers are used, while the models' internal behavior remains poorly understood. We analyzed 13 PLMs across 15 DTs and 9 datasets to assess the value of embeddings from intermediate PLM layers. We trained probe models on embeddings from each layer, compared their performance, and showed that the last layers of PLMs rarely produced embeddings that led to the best results on downstream tasks. Furthermore, we identified a connection between how models learn a certain DT and the similarity between that DT and the pre-training objective. For example, for residue-level downstream tasks, we observed a steady increase in performance across almost all PLM layers, which we attributed to their similarity to most PLMs' pre-training objectives. To allow the community to capitalize on our findings, we provide PLMSommelier, a Python package that automatically identifies the best PLM layer for a given DT with ~98% accuracy and creates a truncated model using only the early layers up to the best-performing layer. This will help users save time and memory during inference and yield better predictive performance.

Modern Protein Language Models (PLMs) apply transformer-based model architectures from natural language processing to biological sequences, predicting a variety of protein functions and properties. However, protein language has key differences from natural language, such as a rich functional space despite a vocabulary of only 20 amino acids. These differences motivate research into how transformer-based architectures operate differently in the protein domain and how we can better leverage PLMs to solve protein-related tasks. In this work, we begin by directly comparing how the distribution of information stored across layers of attention heads differs between the protein and natural language domain. Furthermore, we adapt a simple early-exit technique-originally used in the natural language domain to improve efficiency at the cost of performance-to achieve both increased accuracy and substantial efficiency gains in protein non-structural property prediction by allowing the model to automatically select protein representations from the intermediate layers of the PLMs for the specific task and protein at hand. We achieve performance gains ranging from 0.4 to 7.01 percentage points while simultaneously improving efficiency by over 10 percent across models and non-structural prediction tasks. Our work opens up an area of research directly comparing how language models change behavior when moved into the protein domain and advances language modeling in biological domains.

Protein Language Models (PLMs) have made remarkable progress following scaling laws established in natural language processing across sequence- and structure-based tasks, yet the potential of tokenization remains underexploited. Unlike human language, proteins preserve structure despite extensive sequence variation a property standard tokenization strategies fundamentally fail to capture. We introduce ZEST (Zoned Encoding of Sequence Traits), an evolution-informed vocabulary derived from conserved regions of multiple sequence alignments. ZEST allows embedding domain-level biological priors directly at the tokenization stage rather than learning them implicitly through scale. ZEST natively compresses sequences to an average token length of 4 residues, enabling our model to process 4,000 residues within a standard 1024-token context window. Building on this, we present LEMON (Layered Extraction of Molecular Ordering from Nature), a compact 200M-parameter sequence-based model for detection of remote homology between protein sequences trained on a single H100 GPU for one week. Despite its modest size, LEMON outperforms state-of-the-art models ranging from 600M to 3B parameters. Our results demonstrate that evolution-informed tokenization can substitute for massive parameter scaling, opening a new direction for efficient, biologically-grounded protein representation learning. All code, model weights, and results are publicly available under the MIT license.