MultiGeo: Predicting Drug-Target Affinity via Adaptive Multi-Conformation Ensemble Learning

Abstract

Predicting drug–target affinity (DTA) is central to drug discovery, yet most deep learning models rely on a single static protein structure, neglecting the conformational heterogeneity that underlies many binding mechanisms. We propose MultiGeo, a DTA prediction framework that explicitly leverages multiple protein conformations rather than a single snapshot. For each target, MultiGeo starts from an ensemble of structure predictions and uses confidence scores to adaptively select a small set of high-quality, diverse conformers. A hierarchical structural encoder then extracts multi-scale geometric features from these conformers, which are aggregated by a GRU to obtain an ensemble-level representation. To avoid indiscriminately mixing noisy or redundant views, we introduce a disagreement-aware gating mechanism that adaptively fuses this ensemble representation with the dominant structure only when the additional conformers provide complementary information. Finally, ligand–target interactions are modeled via a block-wise cross-attention module that captures multi-perspective dependencies between ligand and protein features. Extensive experiments on multiple DTA benchmarks demonstrate that MultiGeo consistently outperforms state-of-the-art baselines, showing that explicitly encoding conformational diversity yields more accurate and robust affinity prediction.