Ward Haddadin

Julia Buhmann, Ward Haddadin, Lukáš Pravda et al.

Predicting protein-ligand binding affinity is an essential part of computer-aided drug design. However, generalisable and performant global binding affinity models remain elusive, particularly in low data regimes. Despite the evolution of model architectures, current benchmarks are not well-suited to probe the generalisability of 3D binding affinity models. Furthermore, 3D global architectures such as GNNs have not lived up to performance expectations. To investigate these issues, we introduce a novel split of the PDBBind dataset, minimizing similarity leakage between train and test sets and allowing for a fair and direct comparison between various model architectures. On this low similarity split, we demonstrate that, in general, 3D global models are superior to protein-specific local models in low data regimes. We also demonstrate that the performance of GNNs benefits from three novel contributions: supervised pre-training via quantum mechanical data, unsupervised pre-training via small molecule diffusion, and explicitly modeling hydrogen atoms in the input graph. We believe that this work introduces promising new approaches to unlock the potential of GNN architectures for binding affinity modelling.

Nicholas J. Williams, Ward Haddadin, Matteo P. Ferla et al.

Computational enzyme design requires generating proteins that scaffold catalytic residues and ligands, a task that demands both geometric accuracy and structural diversity from the underlying generative model. Current all-atom generators inherit expensive architectures from structure prediction, leading to high training costs and limited sample diversity. We argue that much of this complexity is unnecessary for generators, which condition on sparse geometric constraints rather than rich co-evolutionary signals. Emyx is a 140M-parameter conditional flow matching model that concentrates capacity within standard transformer blocks, replacing heavy embedding stacks with lightweight conditional representations and sparse connectivity. We additionally derive an exact reparametrisation of the flow matching interpolant into the EDM noise-level framework, bridging flow matching training efficiency with state-of-the-art sampling methods designed for diffusion models without retraining. Despite being the smallest model, Emyx outperforms both Proteína-Complexa and RFdiffusion3 against the AME enzyme design benchmark across success rate under strict evaluation requiring both global fold recovery and catalytic geometry accuracy, structural novelty, scaffold diversity, and geometric validity, while training in just $682$ GPU-hours, roughly $4\times$ less than RFdiffusion3.