Structure-agnostic protein-ligand binding affinity prediction via hierarchical representation alignment

To enable real-world protein-ligand affinity prediction, not only out-of-distribution generalization but also robustness to variable structural availability and quality should be considered in model design.

We present AlignNet, a hierarchical representation alignment framework that mitigates intra- and inter-molecular heterogeneity to learn robust protein-ligand embeddings for generalizable affinity prediction, even from sequence-level inputs. Its intra-molecular module projects unimodal and multimodal features into a unified space, aligning augmented multimodal views for feature fusion and unimodal with multimodal embeddings to distill multimodal priors for structure-agnostic inference. Its inter-molecular module aligns protein and ligand embeddings for cross-molecular integration. Extensive experiments show that AlignNet (i) achieves highly competitive performance, with up to a 20.4% gain in SCC on the challenging LBA 30% split under sequence-only settings, suggesting improved out-of-distribution generalization; and (ii) learns well-separated affinity-related clusters, supporting reliable structure-independent prediction.

AlignNet is available at https://github.com/altriavin/AlignNet.