Towards Generalizable Protein-ligand Co-folding with ACER

Abstract

Predicting protein-ligand complex structures is a central challenge in drug discovery. While recent co-folding models such as AlphaFold-3 achieve accurate structure prediction, they fail to generalize to underexplored binding interfaces - systematically misplacing ligands, particularly for allosteric or structurally novel targets. To address this gap, we present ACER (Adaptive Co-folding via pocket Exploration and pose Ranking), a training-free framework that (a) enables co-folding models to systematically explore alternative binding pockets, and (b) leverages the discovered pockets to increase pose accuracy. Our method enables the efficient discovery of non-prevalent pockets without prior expert knowledge. ACER improves pocket discovery and pose accuracy on allosteric targets and structurally novel complexes, successfully modeling binding interfaces that are under-represented or absent from the training set. Our results demonstrate how improved sampling dynamics enhance the generalisability of co-folding models without retraining.