Boltz-Perturb: Improving Diversity and Accuracy in Protein-Ligand Co-Folding through Training-Free Conditioning Perturbation

Abstract

Protein-ligand co-folding models hold promise in structure-based drug discovery and small molecule interaction prediction, but often fail in predicting correct small molecule binding poses. We present Boltz-Perturb, a framework for addressing this through perturbing model conditioning signals during model inference, and show that such perturbations improve correct ligand binding mode predictions. We first show with true-coordinate injection experiments that the models learned energy landscape contains correct binding-mode basins, allowing us to reframe the problem as one of sampling deficiency. We then introduce two inference-time perturbation strategies, Token Bias Perturbation (TBP) and Token Conditioning Perturbation (TCP), which increase exploration of alternative binding poses. Across diverse protein-ligand systems, TCP improves top-20 oracle success rates by 2.6 to 7.8 fold. Boltz-Perturb attains higher oracle success rates compared to the Boltz-2 high diffusion temperature variant while requiring over 75% less compute. To our knowledge, this is the first systematic perturbation analysis of a co-folding architecture for small-molecule binding mode diversity. We demonstrate that inference-time perturbations can unlock latent structural diversity in generative co-folding models and improve protein-ligand predictions without costly retraining.