Multi-Objective Protein Optimization via Modular Diffusion Steering

Overview & Synopsis

Protein engineering often requires improving several properties simultaneously, motivating the search for high-performing sequences that represent useful fitness tradeoffs. Discovering these sequences is challenging because the design space is combinatorially large and experimental campaigns often permit only a few rounds of batched measurements. We introduce \textit{MODS}, a modular framework for multi-objective protein optimization via inference-time diffusion steering. For each proposal, MODS samples augmented Chebyshev scalarization weights and a fitness-surrogate ensemble member to define a scalar steering reward. Varying the weights directs generation toward different objective tradeoffs, while varying ensemble members diversifies the predictions used for guidance. Because MODS expresses multi-objective acquisition through scalar rewards, it can be paired with different diffusion models and compatible steering procedures. After each evaluation batch, MODS updates the surrogates without retraining the generative model. We evaluate MODS on six protein optimization tasks using predictive oracles trained on experimental assay data, with two diffusion models and two steering procedures. MODS achieves competitive final hypervolume across all six tasks with both diffusion models, and substantially outperforms the best evaluated baseline on several tasks. Our results demonstrate a flexible and effective approach to multi-objective protein optimization with limited feedback.