StabilityArc is a method that decodes protein sequence embeddings into generalizable stability landscapes. It uses a shared RoPE transformer to map frozen ESMC-600M residue representations into an Lx20 matrix of substitution effects, with a symmetric, contact-aware residual to predict epistasis. In extensive leave-one-protein-out tests on 134,794 ProteinGym variants, StabilityArc achieves a Spearman correlation of 0.7134, surpassing the best zero‑shot baseline, and further improves Kermut’s performance when used as a prior.
By Aaron L. Feller, Andrew D. Ellington, Claus O. Wilke
SymFold introduces a symmetric dual‑path architecture that combines protein language models (PLMs) and multimodal protein language models (MPLMs) to iteratively guide protein sequence generation for inverse folding. By leveraging pretrained sequence evolution knowledge from PLMs and structural knowledge from MPLMs, the method improves upon the traditional serial pipeline where structure encoders produce coarse sequences refined by PLMs. Experiments on standard inverse‑folding benchmarks show state‑of‑the‑art performance, and ablation studies confirm the effectiveness of the symmetric design.
By Handong Wang, Jiaxin Qi, Baisheng Lai, Jianqiang Huang
The paper investigates a problem in guided protein language models where strong guidance causes the model’s internal representations to collapse onto a region indistinguishable from random amino‑acid input, leading to low‑complexity sequences that still score well on the targeted property. The authors identify this off‑manifold collapse as a detectable signature and propose a post‑hoc filtering technique—Mahalanobis filtering—that removes atypical candidates based on a density prior over natural activations. This simple, training‑free step improves both property scores and structural plausibility across different guidance methods without altering the generator.
By Shuibai Zhang, Xinchi Liu, Fred Zhangzhi Peng, Zhihan Yang, Shutong Wu, Yingzi Ma, Jiawei Zhang
The paper introduces ORBIT, a framework for probing higher‑order epistasis in protein representations. ORBIT validates Walsh‑based diagnostics on synthetic landscapes, then applies them to the GB1 fitness landscape, comparing several models including ridge regression, MLPs, and Residual Interaction Tokenization (RIT). While no architecture differences were found in overall prediction performance, RIT notably increased pairwise token‑level accessibility, and deeper MLPs improved higher‑order functional recovery, revealing representation‑level changes hidden by conventional metrics.
By Maryam Rahimimovassagh, Ivan Garibay, Niloofar Yousefi
ProtLingo is a protein language modeling framework that enhances a pretrained single‑sequence Transformer backbone with conditional local memory and sparse expert routing. It maps residue representations into discrete codes, composes local windows into latent N‑gram addresses, and retrieves reusable residual signals for recurring sequence contexts. The model also converts selected feed‑forward blocks into sparse Mixture‑of‑Experts layers, allowing residue‑dependent computation while activating only a subset of parameters, achieving competitive performance on protein fitness prediction, FLIP benchmarks, and supervised contact prediction with a 150M‑parameter backbone.
By Mingrui Li, Sixian Shen, Minzhang Li, Ruiyi Zhang, Kexin Zhang, Jiakai Zhang, Jingyi Yu
PFArena is a new benchmark for evaluating language models in protein modification tasks, featuring four controlled interfaces that span single‑mutant generation and multi‑mutant ranking. It incorporates varying levels of mutation fitness data to represent four research scenarios with different amounts of prior experimental context. The benchmark tests six protein language models, six large language models, and five LLM‑based agents, finding that PLMs excel at open‑ended single‑mutant generation while LLMs and agents perform best in multi‑mutant ranking when target‑specific data are available, yet all struggle as search space and mutation depth grow.
By Yawen Ouyang, Xinbo Zhang, Ziyuan Ma, Yixin Wu, Wenbin Liao, Feiran Zhang, Wenjie Li, Lihao Wang, Hao Wang, Xiaoqing Zheng, Xuefeng Yan, Lei Bai, Ya-Qin Zhang, Shuyi Zhang, Wei-Ying Ma, Dahua Lin, Bowen Zhou, Hao Zhou
The paper investigates how guided protein language models can collapse onto off‑manifold representations when heavily steered to optimize a property. This collapse causes generated sequences to become low‑complexity and statistically similar to random amino‑acid input, yet the property oracle may still rate them highly. The authors propose a cheap, training‑free Mahalanobis filtering step that removes such off‑manifold candidates, improving both property scores and structural plausibility without altering the generator.
arXiv:2606. 18961v1 Announce Type: new Abstract: Protein language models (PLMs) have emerged as powerful tools for controllable biomolecular design, yet their post-training adaptation typically relies on costly wet-lab validation or curated preference datasets.
By Lanqing Li, Shentong Mo, Yang Yu, Pheng-Ann Heng
The study evaluates 4‑bit quantization and low‑rank adapter fine‑tuning (QLoRA) on several large protein language models, finding that many model‑task pairs retain over 90% of full fine‑tuning performance while achieving up to 90% GPU memory savings. QLoRA preserves early‑layer representations and induces task‑specific changes in later layers, closely resembling full fine‑tuning with smaller representational shifts. For generative models, 4‑bit quantization largely maintains structural and sequence‑level properties, though token‑level analysis reveals model‑dependent changes in autoregressive output distributions.
By Ilan Yaniv Zeisler, Sebastian Clancy, Pouriya Bayat, Saaim Raad, Ivan Kraskov, Matthew Xie, Vivian White, Spencer Perkins, Serena Singh, Sepehr Bayat, Keith Pardee
arXiv:2506. 07459v4 Announce Type: replace Abstract: Protein generative models have shown remarkable promise in protein design, yet their success rates remain constrained by reliance on curated sequence-structure datasets and by misalignment between supervised objectives and real design goals.
By Ziwen Wang, Jiajun Fan, Ruihan Guo, Thao Nguyen, Heng Ji, Ge Liu
arXiv:2605. 00182v3 Announce Type: replace Abstract: Proteins are shaped by gradual evolution under biophysical and functional constraints.
By Xinyou Wang, Liang Hong, Jiasheng Ye, Zaixiang Zheng, Yu Li, Shujian Huang, Quanquan Gu
arXiv:2507. 08920v4 Announce Type: replace-cross Abstract: We introduce AMix-1, a powerful protein foundation model built on Bayesian Flow Networks and empowered by a systematic training methodology, encompassing pretraining scaling laws, emergent capability analysis, in-context learning mechanism, and test-time scaling algorithm.
By Changze Lv, Jiang Zhou, Siyu Long, Lihao Wang, Jiangtao Feng, Dongyu Xue, Yu Pei, Hao Wang, Zherui Zhang, Yuchen Cai, Zhiqiang Gao, Ziyuan Ma, Jiakai Hu, Chaochen Gao, Jingjing Gong, Yuxuan Song, Shuyi Zhang, Xiaoqing Zheng, Deyi Xiong, Lei Bai, Wanli Ouyang, Ya-Qin Zhang, Wei-Ying Ma, Bowen Zhou, Hao Zhou