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

Molecular optimization is commonly performed under a limited oracle budget, which makes deciding what to evaluate as important as deciding what to generate. We introduce short-term graph memory, a plug-in module that preserves the generator architecture and native update rule while learning from previously evaluated molecules to prioritize subsequent oracle queries. The module maintains an online graph neural surrogate that pre-screens each round's candidate pool, so the fixed oracle budget is spent on molecules with higher predicted utility. Applied to a fragment-based generator on a standard molecular optimization benchmark, it improves the mean top-10 score at no extra oracle cost and never falls behind the base on any oracle; the gain extends to all four generators we tested at a tight budget of one thousand calls. We then analyze how surrogate-guided selection interacts with the exploration and exploitation behavior of different generators. Its benefit at larger budgets is consistent with two properties of the backbone: how broadly it searches, and how effectively its native search already exploits oracle feedback. We provide a simple way to spend a fixed oracle budget more selectively, and evidence on which generators benefit from it.

Protein sequence optimization under tight oracle budgets requires methods that explore vast combinatorial spaces while making each evaluation informative. Existing reinforcement learning and off-policy generative approaches often degrade under surrogate noise, and position-agnostic mutation proposals risk disrupting functionally critical residues. We introduce SILO, a trajectory-level self-improvement imitation framework for oracle-budgeted protein design. SILO uses a hierarchical edit policy that decomposes each mutation into a position choice followed by a residue choice. In each active-learning round, the policy samples candidate trajectories via incremental stochastic beam search without replacement (SBS), and a UCB-based proxy ensemble, combined with an alanine-scan fitness score (AFS), selects candidates with functionally relevant edits for in silico oracle evaluation. The policy is then updated by next-action cross-entropy imitation on the round's best oracle-labeled trajectories, avoiding value-function estimation. Across eight reproduced protein fitness landscapes and five strong baselines from prior work, SILO achieves the highest maximum and top-100 mean fitness on 8 of 8 landscapes within our evaluations, often exhibiting faster early-stage improvement. In low-data and noisy-proxy stress tests on two landscapes per setting, SILO remains competitive or best when several baselines degrade. Ablations show that SBS with AFS account for much of the gains, with iterative imitation providing additional improvement. Code is available at: https://github.com/grimmlab/SILO.git

Standard evaluation of large language models assumes stable model rankings across inference conditions. We challenge this assumption by varying the token generation budget, i.e., the maximum tokens a model may produce, across seven levels (64--4,096), evaluating four models on three reasoning benchmarks (56,476 inferences). We report four findings: (i) 3--19% of items exhibit non-monotone behavior (accuracy decreasing with more budget), even after controlling for truncation, and this phenomenon is model-specific (cross-model overlap: 6--14%). (ii) Model rankings reverse across budgets on all benchmarks ($p {<} 0.01$, McNemar). (iii) Oracle analysis reveals model complementarity up to $+27.8$pp, most pronounced at constrained budgets. (iv) A budget-aware router captures 14.1% of the oracle gap cross-domain; budget features help within-domain ($+1.6$ to $+5.7$pp) but are domain-specific and hurt transfer ($-1.2$pp). These results argue for budget-conditioned evaluation protocols.