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原文摘要

Protein variant effect prediction is central to understanding protein function and guiding protein engineering, yet experimental labels remain costly. In many protein experiments, the variants that can be assayed are dictated by protocol constraints, while the variants that need accurate prediction may lie in a different or broader region of the landscape. This assay-prediction mismatch makes candidate-local criteria such as predicted function, uncertainty, or exploration value insufficient for measurement design. Given a protocol-defined accessible space and a limited budget, we ask which variants should be assayed so that the resulting data best improves landscape prediction. We propose TALK, which estimates each candidate's contribution through posterior coupling between accessible and target variants and reduces redundant information within the batch. Across retrospective ProteinGym and FLIP protocols, TALK generally improves target-space prediction under limited measurement budgets. These results point to a practical two-stage workflow: first, spend a limited assay budget on variants selected to be informative for the target landscape and train a predictive model from the measured labels; then use this model to score and prioritize high-potential variants. Code is available at https://github.com/joehuang618/TALK.