How to Spend Your Oracle Budget: Practical Guidance for Protein Structure Prediction Models

Foundation models for protein structure prediction remain unreliable on certain targets. External oracles can flag and correct these failures, but biological oracles are expensive, making oracle budget a critical constraint. Existing guidance methods, such as FK-steering, DPO, and Best K-of-N sampling, differ in how they spend this budget, yet no systematic comparison exists to guide method selection. To bridge this gap, we benchmark these methods alongside the recently proposed Optimisation Over Outputs (O3), which applies off-the-shelf optimisers within a generative model's latent subspace. We extend the usage of O3 to protein structure prediction models. Overall, our work provides the first practical reference for oracle budget-aware guidance. Our evaluation on two protein targets, calmodulin (1CLL) and E. coli aspartate transcarbamoylase (9EEH), reveals that no single method consistently dominates across all budgets and oracles. Specifically, O3 proves most effective at low oracle budgets, while FK-steering and DPO demonstrate improved performance as the budget increases. We distil these findings into actionable recommendations for practitioners operating under real-world oracle-budget constraints.

Lyapunov Guidance: A Unified Framework for Stabilizing Generative Flows

Flow matching has emerged as an effective framework for learning complex data distributions, but adapting pretrained flow models to new tasks often requires computationally expensive retraining. Post-training guidance provides a more efficient alternative, but existing methods are largely heuristic and offer no explicit stability guarantees. We address this limitation by proposing LyaGuide, a unified Lyapunov-guided framework that formulates flow guidance as a Lyapunov control problem. Our main theoretical result establishes an equivalence between guided flow matching and Lyapunov control, thereby unifying common guidance strategies, such as classifier guidance, reward guidance, and energy-based guidance, within a single control-theoretic framework. To enforce the Lyapunov condition, we introduce a pseudo-projection operator with a closed-form expression that endows learned or heuristic guidance terms with explicit stability guarantees. LyaGuide supports two practical settings: a model-driven setting, where the target guidance distribution is specified through a known Lyapunov function, and a data-driven setting, where the guidance is adapted from task-specific downstream data. LyaGuide is compatible with existing guidance methods, introduces minimal additional computational overhead, and is straightforward to integrate in practice. Extensive experiments on synthetic benchmarks, image inverse problems, reinforcement learning planning, and energy-based modeling demonstrate consistent improvements in sample quality, guidance fidelity, and robustness, while maintaining computational efficiency.

GuidedBridge: Training-freely Improving Bridge Models with Prior Guidance

Guidance methods, such as classifier-free guidance (CFG) and auto-guidance (AG), have advanced noise-to-data generation in diffusion models. Recently, bridge models have introduced a data-to-data generative process that can exploit an instructive clean prior. In this work, inspired by previous methods creating quality difference between denoising results as guidance, we propose a training-free bridge guidance method, termed Prior Guidance (PG). Specifically, we introduce a weak prior, which is unseen during bridge pre-training, hindering prior exploitation and thereby degrading denoising result. Then, we contrast it with the seen prior to highlight and enhance prior exploitation via a scaling factor. Moreover, we analyze the underlying mechanism of prior exploitation in the bridge process and design frequency-modulated prior guidance (FMPG), which tailors the guidance scale to low- and high-frequency bands coherent with bridge generative dynamics. To address prior exploitation in image in-painting, we develop a cascaded framework, CFG-FMPG, which first generates a noisy hidden representation via CFG and then exploits it as a generative prior with FMPG, fulfilling their complementary strengths without compromising inference efficiency. Experiments demonstrate that our PG methods consistently improve pre-trained bridge models across diverse image translation tasks.