Existing cell embedding methods predominantly rely on transcriptomic or proteomic measurements and represent each cell as a holistic entity, thereby overlooking the subcellular localization of individual molecules. Moreover, they rarely incorporate protein structural information, despite its fundamental role in determining molecular interactions and functions. In this work, we propose a multimodal framework for learning subcellularly resolved cell embeddings by jointly leveraging RNA expression profiles, protein sequence representations, and protein structural information. Specifically, we employ a cross-attention architecture to integrate transcriptomic, sequence, and structural modalities and model their interactions within distinct subcellular compartments. The resulting embeddings represent each cell through its fine-grained subcellular organization, capturing both molecular expression patterns and the functional properties of the associated proteins. By learning cell representations at subcellular resolution, our framework preserves spatially organized biological information while integrating complementary signals across multiple molecular levels. To the best of our knowledge, this is the first framework that produces subcellularly resolved cell embeddings by jointly incorporating transcriptomic information, protein sequence representations, and protein structural knowledge within a unified cross-modal learning paradigm.
Antibody-specific epitope prediction aims to identify which antigen residues are recognized by a given antibody, a task that depends on the three-dimensional complementarity between antibody CDRs and the antigen surface. Existing methods usually leverage PLM embeddings and inject structure through additional graph, surface, or point-cloud encoders, where the positional mechanism inside attention remains largely tied to one-dimensional sequence order. For proteins, the analogue of a token offset is not only sequence separation, but also the three-dimensional displacement between residues after folding. This raises a question, can folded residue geometry serve as the positional mechanism of attention itself? We propose Local-Frame 3D Rotary Position Encoding (LF3DRoPE), which expresses inter-residue displacements in backbone-defined local frames and injects them directly into rotary attention. This design preserves continuous directional geometry while ensuring invariance to global $\mathrm{SE}(3)$ transformations. On the AsEP benchmark, LF3DRoPE achieves state-of-the-art $\mathrm{MCC}$ on both ratio and epitope-group splits. Ablations and rigid transformation tests show that local three-dimensional geometry provides information beyond sequence-order attention while preserving invariance to arbitrary global coordinate systems. Mutation ranking results further indicate that LF3DRoPE captures antigen-specific structural compatibility.
AlphaFold2's 93 million parameters, shaped by the evolutionary record of protein structure encoded in the Protein Data Bank and in sequence alignments, are conventionally treated only as machinery for converting sequence to structure. We propose they are also a scientific object that can be analyzed directly: a learned encoding of protein conformational organization that can be probed and characterized. By smoothing the Evoformer's weight tensors with a Gaussian convolution and scaling the result, we show that the trained model produces physically structured conformational landscapes. Under perturbation, ubiquitin's native contacts break in the order established by decades of folding experiments. For KaiB, five independently trained models agree that the alternative fold is not recovered under perturbation. For alpha-synuclein, five models produce five different but coherent landscapes, mapping where the training signal has determined the representation and where it has not. Matched-power noise controls confirm that random corruption of equal magnitude produces debris, not conformations. The model learned to predict static structures; the conformational organization visible under perturbation was not an explicit training target, suggesting it emerged as a byproduct of that objective. AlphaFold2's weights appear to encode structural constraints, shaped by evolutionary and structural training data, that extend beyond what unperturbed inference reveals. We call the approach of reading them neural spectroscopy, and Scaled Gaussian Convolution one such protocol.
Giosue Migliorini, Aristofanis Rontogiannis, Grigori Guitchounts +3cs.LG
Foundation models for structural biology have achieved remarkable performance in predicting biomolecular structure and show promise for the design of proteins and small molecules. Yet understanding which internal features drive their outputs remains challenging. Standard sparse autoencoders (SAEs), effective on transformer-style sequence embeddings, do not transfer cleanly to pairformer-like architectures: naively operating on pairwise representations yields a quadratic blow-up of features and obscures concepts distributed jointly across sequence and pair representations. We introduce PairSAE, which summarizes pairwise tensors via an N-mode SVD into token-wise interaction roles, then uses a sparse autoencoder to learn a shared set of token-level features that decode into both sequence and pair representations. Evaluated on Boltz-2 activations for PLINDER protein-ligand complexes, PairSAE yields interpretable features that align with UniProt annotations and predict Boltz-2 affinity values. These results indicate that PairSAE links the latent space of foundation models for structural biology to interpretable structural concepts, clarifying what the model "knows" while avoiding pairformer-induced pitfalls that limit conventional SAEs.