Protein Thoughts: Interpretable Reasoning with Tree of Thoughts and Embedding-Space Flow Matching for Protein-Protein Interaction Discovery
Authors: Kingsley Yeon, Xuefeng Liu, Promit Ghosal
Summary
arXiv:2605. 21522v1 Announce Type: cross Abstract: Protein-protein interactions (PPIs) govern nearly all cellular processes, yet computational methods for identifying binding partners typically produce ranked predictions without mechanistic justification.
Relevance
Read next because Protein Thoughts: Interpretable Reasoning with Tree of Thoughts and Embedding-Space Flow Matching for Protein-Protein Interaction Discovery overlaps with clean result "LoRA persona trained on alone emits at 23.5% when a co-trained partner learns ..., vs 0% control on Qwen2.5-7B-Instruct (MODERATE confidence)", clean result "Leakage rate is a usable signal for recovering trigger-shaped phrases on Gaperon-1125-1B without knowing the hidden trigger itself (MODERATE confidence)", clean result "Language-mismatch LoRA SFT on Qwen2.5-7B leaks the trained completion language into bystander directives the model was never trained on, absent under same-language SFT (LOW confidence)". Matching terms: text, class, rect, directive, line, rate, without, binding. Source: arxiv stat.ML (Machine Learning).
Threat model
Potential threat/caveat for clean result "LoRA persona trained on alone emits at 23.5% when a co-trained partner learns ..., vs 0% control on Qwen2.5-7B-Instruct (MODERATE confidence)": this item discusses benchmark.
Abstract
arXiv:2605.21522v1 Announce Type: cross Abstract: Protein-protein interactions (PPIs) govern nearly all cellular processes, yet computational methods for identifying binding partners typically produce ranked predictions without mechanistic justification. This creates a fundamental barrier to adoption because biologists cannot assess whether predictions reflect genuine biochemical insight or spurious correlations. We present \textbf{Protein Thoughts}, a framework that reformulates PPI discovery as an interpretable search problem with explicit reasoning. The system decomposes binding evidence into four biologically meaningful signals: sequence similarity reflecting evolutionary relationships, structural complementarity capturing geometric fit, interface balance, and chemical compatibility encoding residue-level interactions. Rather than collapsing these signals into an opaque score, we preserve their individual contributions through a transparent value function that enables both ranking and auditing. To navigate large candidate spaces efficiently, we introduce hypothesis-guided entropy-regularized Tree-of-Thoughts search. A fine-tuned language model generates search directives from embedding-derived features, classifying candidates as high-priority, exploratory, or skippable. These directives condition a Boltzmann policy that balances exploitation with entropy-driven exploration, while hypothesis-aware pruning prevents premature abandonment of promising candidates. For candidates exhibiting score disagreement, hypothesis-conditioned embedding-space flow matching transports protein embeddings toward the binder manifold. On the SHS148k benchmark, Protein Thoughts achieves mean best-binder rank of 11.2 versus 47.7 for an entropic tree search baseline, a 76% improvement, and for binding prediction the trained value function achieves $91.08 \pm 0.19$ Micro-F1, outperforming existing PPI methods on the same dataset.