# Structure-Aligned Protein Language Model

arXiv: https://arxiv.org/abs/2505.16896 · HTML: https://mlsanity.com/paper/2505.16896/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 16 of its 46 references that are in the map.
- First posted on arXiv 22 May 2025.

## Builds on (most cited first, 16 of 16)

- [BERT: Pre-training of Deep Bidirectional Transformers for Language Understanding](https://mlsanity.com/paper/1810.04805/) (2018)
- [Learning Transferable Visual Models From Natural Language Supervision](https://mlsanity.com/paper/2103.00020/) (2021)
- [Language Models are Few-Shot Learners](https://mlsanity.com/paper/2005.14165/) (2020)
- [UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction](https://mlsanity.com/paper/1802.03426/) (2018)
- [Prioritized Training on Points that are Learnable, Worth Learning, and Not Yet Learnt](https://mlsanity.com/paper/2206.07137/) (2022)
- [A Survey on Data Selection for Language Models](https://mlsanity.com/paper/2402.16827/) (2024)
- [Evaluating Protein Transfer Learning with TAPE](https://mlsanity.com/paper/1906.08230/) (2019)
- [Protein Representation Learning by Geometric Structure Pretraining](https://mlsanity.com/paper/2203.06125/) (2022)
- [PEER: A Comprehensive and Multi-Task Benchmark for Protein Sequence Understanding](https://mlsanity.com/paper/2206.02096/) (2022)
- [xTrimoPGLM: Unified 100B-Scale Pre-trained Transformer for Deciphering the Language of Protein](https://mlsanity.com/paper/2401.06199/) (2024)
- [DeepSF: deep convolutional neural network for mapping protein sequences to folds](https://mlsanity.com/paper/1706.01010/) (2017)
- [Structure-aware Protein Self-supervised Learning](https://mlsanity.com/paper/2204.04213/) (2022)
- [Exploring evolution-aware & -free protein language models as protein function predictors](https://mlsanity.com/paper/2206.06583/) (2022)
- [Endowing Protein Language Models with Structural Knowledge](https://mlsanity.com/paper/2401.14819/) (2024)
- [Structure-Informed Protein Language Model](https://mlsanity.com/paper/2402.05856/) (2024)
- [CCPL: Cross-modal Contrastive Protein Learning](https://mlsanity.com/paper/2303.11783/) (2023)

## Built on by (most cited first, 1 of 1)

- [Does Learning Protein Folding Generalize to Broader Reasoning?](https://mlsanity.com/paper/2609.38879/) (2026)

## Abstract (arXiv)

Protein language models (pLMs) pre-trained on vast protein sequence databases excel at various downstream tasks but often lack the structural knowledge essential for some biological applications. To address this, we introduce a method to enrich pLMs with structural knowledge by leveraging pre-trained protein graph neural networks (pGNNs). First, a latent-level contrastive learning task aligns residue representations from pLMs with those from pGNNs across multiple proteins, injecting inter-protein structural information. Additionally, a physical-level task integrates intra-protein information by training pLMs to predict structure tokens. Together, the proposed dual-task framework effectively incorporates both inter- and intra-protein structural knowledge into pLMs. Given the variability in the quality of protein structures in PDB, we further introduce a residue loss selection module that uses a small model trained on high-quality structures to select reliable yet challenging residue losses for the pLM to learn. Applying our structure alignment method as a simple, lightweight post-training step to the state-of-the-art ESM2 and AMPLIFY yields notable performance gains. These improvements are consistent across a wide range of tasks, including substantial gains in deep mutational scanning (DMS) fitness prediction and a 59% increase in P@L for ESM2 650M contact prediction on CASP16. Furthermore, we demonstrate that these performance gains are robust, scaling with model sizes from 8M to 650M and extending to different downstream tasks.