Daily Papers

AlphaFold 3 predicts protein structures with remarkable accuracy, yet how structural information emerges within the model remains poorly understood. Here, through causal interventions on internal representations and direct probing of every Pairformer block, we trace the formation of global protein geometry and identify the multiple sequence alignment (MSA) as a structural shortcut to the fold. Removing the MSA largely preserves local secondary structure while disrupting the long-range relationships that define global topology. Restoring the MSA-enriched pair representation at only forty residues recovers most of this lost organization, including at pairs never directly modified. This contribution depends on the detailed direction of the MSA module's output rather than its magnitude. The Pairformer rapidly converts this signal into global geometry: the final fold becomes recoverable by approximately block 9 of 48 for a majority of proteins, roughly twenty-seven blocks before the model's decoder can render it, whereas without the MSA it remains inaccessible for most proteins throughout the pass. Which homologs are supplied shapes this trajectory more strongly than which query is supplied; it persists for a designed query that never evolved but collapses for a shuffled sequence. Most importantly, an alignment built for a different protein that shares the fold, supplied only at the structurally corresponding columns, raises the median TM-score against experiment from 0.44 to 0.72, while the same alignment shifted a few residues along the chain performs worse than supplying no alignment at all. What AlphaFold 3 reads from an alignment is therefore a description of the fold itself, transferable between proteins that share one, rather than the query's own evolutionary history. This explains both its accuracy and the limits of what it has solved.

AlphaFold has transformed protein structure prediction, but emerging applications such as virtual ligand screening, proteome-wide folding, and de novo binder design demand predictions at a massive scale, where runtime and memory costs become prohibitive. A major bottleneck lies in the Pairformer backbone of AlphaFold3-style models, which relies on computationally expensive triangular primitives-especially triangle attention-for pairwise reasoning. We introduce Pairmixer, a streamlined alternative that eliminates triangle attention while preserving higher-order geometric reasoning capabilities that are critical for structure prediction. Pairmixer substantially improves computational efficiency, matching state-of-the-art structure predictors across folding and docking benchmarks, delivering up to 4x faster inference on long sequences while reducing training cost by 34%. Its efficiency alleviates the computational burden of downstream applications such as modeling large protein complexes, high-throughput ligand and binder screening, and hallucination-based design. Within BoltzDesign, for example, Pairmixer delivers over 2x faster sampling and scales to sequences ~30% longer than the memory limits of Pairformer.

Highly accurate biomolecular structure prediction is a key component of developing biomolecular foundation models, and one of the most critical aspects of building foundation models is identifying the recipes for scaling the model. In this work, we present SeedFold, a folding model that successfully scales up the model capacity. Our contributions are threefold: first, we identify an effective width-scaling strategy for the Pairformer to increase representation capacity; second, we introduce a novel linear triangular attention that reduces computational complexity to enable efficient scaling; finally, we construct a large-scale distillation dataset to substantially enlarge the training set. Experiments on FoldBench show that SeedFold outperforms AlphaFold3 on most protein-related tasks.

Lightweight inference is critical for biomolecular structure prediction and other downstream tasks, enabling efficient real-world deployment and inference-time scaling for large-scale applications. In this work, we address the challenge of balancing model efficiency and prediction accuracy by making several key modifications, 1) Multi-step AF3 sampler is replaced by a few-step ODE sampler, significantly reducing computational overhead for the diffusion module part during inference; 2) In the open-source Protenix framework, a subset of pairformer or diffusion transformer blocks doesn't make contributions to the final structure prediction, presenting opportunities for architectural pruning and lightweight redesign; 3) A model incorporating an ESM module is trained to substitute the conventional MSA module, reducing MSA preprocessing time. Building on these key insights, we present Protenix-Mini, a compact and optimized model designed for efficient protein structure prediction. This streamlined version incorporates a more efficient architectural design with a two-step Ordinary Differential Equation (ODE) sampling strategy. By eliminating redundant Transformer components and refining the sampling process, Protenix-Mini significantly reduces model complexity with slight accuracy drop. Evaluations on benchmark datasets demonstrate that it achieves high-fidelity predictions, with only a negligible 1 to 5 percent decrease in performance on benchmark datasets compared to its full-scale counterpart. This makes Protenix-Mini an ideal choice for applications where computational resources are limited but accurate structure prediction remains crucial.