arXiv:2606. 02624v1 Announce Type: cross Abstract: AI for scientific discovery is entering an agentic era, where protein-engineering systems are expected to prioritize future wet-lab experiments rather than merely fit static measurements.
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.
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.
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.
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. To overcome this supervision bottleneck, we introduce unsupervised reward optimization of PLMs, a comprehensive framework for steerable protein generation without ground-truth labels.
arXiv:2609.00189v1 Announce Type: new Abstract: Goal-directed optimization is essential for steering molecular generators to propose candidates with desired properties. However, it is often implement...
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.
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.
VGAS: Variance-Reduced Guidance and Adaptive Selection for Training-Free Reward Alignment in Discrete Diffusion proposes a new inference-time framework that improves steering of frozen masked discrete diffusion models. By reducing the variance of guidance estimates, applying reward tilting to clean-token logits, and adapting the selection temperature at each step, VGAS addresses three default choices in existing pipelines. Experiments on regulatory DNA, protein, and small-molecule benchmarks show that VGAS achieves the best training-free reward performance and matches or surpasses reward-fine-tuned generators.
Protein modification requires navigating an immense sequence space, yet wet-lab validation remains low-throughput and costly. Although computational paradigms including protein language models (PLMs),...
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.
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.