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arXiv Machine Learning

Beyond Tokens: Probing Higher-Order Epistasis in Learned Protein Representations

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.

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arXiv Machine Learning
Jun 9

Constraint-Aware Optimization for Robust Protein Stability Prediction

arXiv:2606. 08100v1 Announce Type: new Abstract: Multimodal $\Delta\Delta G$ predictors integrating protein language models with inverse-folding representations achieve strong in-distribution accuracy on the Megascale dataset but exhibit limited robustness on out-of-distribution (OOD) proteins, persistent forward-reverse bias on paired-mutation benchmarks, and under-representation of rare stabilizing mutations.

By A Shivram, Aneesh S. Chivukula, Manik Gupta, Sourav Chowdhury
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arXiv Machine Learning
Sep 17

Q-BIOLAT: Binary Latent Protein Fitness Landscapes for QUBO-Based Optimization

Q-BIOLAT is a framework that converts pretrained protein-language-model embeddings into compact binary codes and trains a quadratic unconstrained binary optimization (QUBO) surrogate with unary and pairwise latent interactions for protein fitness optimization. The study demonstrates that binary encodings with similar predictive accuracy can produce different Hamming neighborhoods, affecting local optima and search trajectories, and shows that PCA followed by per‑coordinate median thresholding yields a more balanced binary space than AE/VAE baselines. Experimental evaluation on GFP and AAV fitness landscapes from ProteinGym confirms that simulated annealing, genetic algorithms, and greedy hill climbing can retrieve high‑percentile variants, with decoded candidates reported via surrogate‑predicted scores.

By Truong-Son Hy
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arXiv Machine Learning
Jul 7

On the Design Space of Discrete Diffusion Online Adaptation for Molecular Optimization

arXiv:2607. 02834v1 Announce Type: new Abstract: Molecular optimization often starts from a pretrained generative model that captures a broad prior over valid molecular structures.

By Trevor Chen, Ariel Dai, Jason Yang, Riccardo De Santi, Daniel Khalil, Wenda Chu, Nate Gruver, Pranav Murugan, Alexander F. G. Goldberg, Maruan Al-Shedivat, Yisong Yue
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arXiv Machine Learning
Aug 21

ProteinZero: Self-Improving Protein Generation via Online Reinforcement Learning

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
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