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Workshop: 2nd Generative AI for Biology Workshop

ProVADA: Generation of Subcellular Protein Variants via Ensemble-Guided Test-Time Steering

Wenhui Lu · Xiaowei Zhang · L. Mille-Fragoso · Haoyu Dai · Xiaojing Gao · Wong

Keywords: [ sequential importance sampling ] [ protein variant design ] [ generative prior ] [ protein engineering ] [ population-annealing ] [ subcellular localization ]


Abstract:

Engineering protein variants to function in exogenous environments remains a significant challenge due to the complexity of sequence and fitness landscapes. Experimental strategies often require extensive labor and domain expertise. While recent advances in protein generative modeling offer a promising in silico alternative, many of these methods rely on differentiable fitness predictors, which limits their applicability. To this end, we introduce Protein Variant ADAptation (ProVADA), an ensemble-guided, test-time steering framework that combines implicit generative priors with fitness oracles via a composite functional objective. ProVADA leverages Mixture-Adaptation Directed Annealing (MADA), a novel sampler integrating population-annealing, adaptive mixture proposals, and directed local mutations. Furthermore, ProVADA requires no gradients or explicit likelihoods, yet efficiently concentrates sampling on high‐fitness, low-divergence variants. We demonstrate its effectiveness by redesigning human renin for cytosolic functionality. Our results achieve significant gains in predicted localization fitness while preserving structural integrity.

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