Additionally, convolutions are executed on nodes and edges simultaneously to generate comprehensive protein embeddings.

Accurate protein function prediction requires integrating heterogeneous intrinsic signals (e.g., sequence and structure) with noisy extrinsic contexts (e.g., protein-protein interactions and GO term annotations). However, two key challenges hinder effective fusion: (i) cross-modal distributional mismatch among embeddings produced by pre-trained intrinsic encoders, and (ii) noisy relational graphs of extrinsic data that degrade GNN-based information aggregation. We propose Diffused and Aligned Multi-modal Protein Embedding (DAMPE), a unified framework that addresses these through two core mechanisms. First, we propose Optimal Transport (OT)-based representation alignment that establishes correspondence between intrinsic embedding spaces of different modalities, effectively mitigating cross-modal heterogeneity. Second, we develop a Conditional Graph Generation (CGG)-based information fusion method, where a condition encoder fuses the aligned intrinsic embeddings to provide informative cues for graph reconstruction. Meanwhile, our theoretical analysis implies that the CGG objective drives this condition encoder to absorb graph-aware knowledge into its produced protein representations. Empirically, DAMPE outperforms or matches state-of-the-art methods such as DPFunc on standard GO benchmarks, achieving AUPR gains of 0.002-0.013 pp and Fmax gains 0.004-0.007 pp. Ablation studies further show that OT-based alignment contributes 0.043-0.064 pp AUPR, while CGG-based fusion adds 0.005-0.111 pp Fmax. Overall, DAMPE offers a scalable and theoretically grounded approach for robust multi-modal protein representation learning, substantially enhancing protein function prediction.

Protein representation learning is critical for numerous biological tasks. Recently, large transformer-based protein language models (pLMs) pretrained on large scale protein sequences have demonstrated significant success in sequence-based tasks. However, pLMs lack structural context. Conversely, graph neural networks (GNNs) designed to leverage 3D structural information have shown promising generalization in protein-related prediction tasks, but their effectiveness is often constrained by the scarcity of labeled structural data. Recognizing that sequence and structural representations are complementary perspectives of the same protein entity, we propose a multimodal bidirectional hierarchical fusion framework to effectively merge these modalities. Our framework employs attention and gating mechanisms to enable effective interaction between pLMs-generated sequential representations and GNN-extracted structural features, improving information exchange and enhancement across layers of the neural network. This bidirectional and hierarchical (Bi-Hierarchical) fusion approach leverages the strengths of both modalities to capture richer and more comprehensive protein representations. Based on the framework, we further introduce local Bi-Hierarchical Fusion with gating and global Bi-Hierarchical Fusion with multihead self-attention approaches. Our method demonstrates consistent improvements over strong baselines and existing fusion techniques in a variety of protein representation learning benchmarks, including enzyme EC classification, model quality assessment, protein-ligand binding affinity prediction, protein-protein binding site prediction, and B cell epitopes prediction. Our method establishes a new state-of-the-art for multimodal protein representation learning, emphasizing the efficacy of Bi-Hierarchical Fusion in bridging sequence and structural modalities.

Given the vastness of chemical space and the ongoing emergence of previously uncharacterized proteins, zero-shot compound-protein interaction (CPI) prediction better reflects the practical challenges and requirements of real-world drug development. Although existing methods perform adequately during certain CPI tasks, they still face the following challenges: (1) Representation learning from local or complete protein sequences often overlooks the complex interdependencies between subsequences, which are essential for predicting spatial structures and binding properties. (2) Dependence on large-scale or scarce multimodal protein datasets demands significant training data and computational resources, limiting scalability and efficiency. To address these challenges, we propose a novel approach that pretrains protein representations for CPI prediction tasks using subsequence reordering, explicitly capturing the dependencies between protein subsequences. Furthermore, we apply length-variable protein augmentation to ensure excellent pretraining performance on small training datasets. To evaluate the model's effectiveness and zero-shot learning ability, we combine it with various baseline methods. The results demonstrate that our approach can improve the baseline model's performance on the CPI task, especially in the challenging zero-shot scenario. Compared to existing pre-training models, our model demonstrates superior performance, particularly in data-scarce scenarios where training samples are limited. Our implementation is available at https://github.com/Hoch-Zhang/PSRP-CPI.

Kinetic parameters such as the turnover number ($k_{cat}$) and Michaelis constant ($K_{\mathrm{M}}$) are essential for modelling enzymatic activity but experimental data remains limited in scale and diversity. Previous methods for predicting enzyme kinetics typically use mean-pooled residue embeddings from a single protein language model to represent the protein. We present KinForm, a machine learning framework designed to improve predictive accuracy and generalisation for kinetic parameters by optimising protein feature representations. KinForm combines several residue-level embeddings (Evolutionary Scale Modeling Cambrian, Evolutionary Scale Modeling 2, and ProtT5-XL-UniRef50), taken from empirically selected intermediate transformer layers and applies weighted pooling based on per-residue binding-site probability. To counter the resulting high dimensionality, we apply dimensionality reduction using principal--component analysis (PCA) on concatenated protein features, and rebalance the training data via a similarity-based oversampling strategy. KinForm outperforms baseline methods on two benchmark datasets. Improvements are most pronounced in low sequence similarity bins. We observe improvements from binding-site probability pooling, intermediate-layer selection, PCA, and oversampling of low-identity proteins. We also find that removing sequence overlap between folds provides a more realistic evaluation of generalisation and should be the standard over random splitting when benchmarking kinetic prediction models.

We develop ProxelGen, a protein structure generative model that operates on 3D densities as opposed to the prevailing 3D point cloud representations. Representing proteins as voxelized densities, or proxels, enables new tasks and conditioning capabilities. We generate proteins encoded as proxels via a 3D CNN-based VAE in conjunction with a diffusion model operating on its latent space. Compared to state-of-the-art models, ProxelGen's samples achieve higher novelty, better FID scores, and the same level of designability as the training set. ProxelGen's advantages are demonstrated in a standard motif scaffolding benchmark, and we show how 3D density-based generation allows for more flexible shape conditioning.

Computational prediction of enzymatic reactions represents a crucial challenge in sustainable chemical synthesis across various scientific domains, ranging from drug discovery to materials science and green chemistry. These syntheses rely on proteins that selectively catalyze complex molecular transformations. These protein catalysts exhibit remarkable substrate adaptability, with the same protein often catalyzing different chemical transformations depending on its molecular partners. Current approaches to protein representation in reaction prediction either ignore protein structure entirely or rely on static embeddings, failing to capture how proteins dynamically adapt their behavior to different substrates. We present Docking-Aware Attention (DAA), a novel architecture that generates dynamic, context-dependent protein representations by incorporating molecular docking information into the attention mechanism. DAA combines physical interaction scores from docking predictions with learned attention patterns to focus on protein regions most relevant to specific molecular interactions. We evaluate our method on enzymatic reaction prediction, where it outperforms previous state-of-the-art methods, achieving 62.2\% accuracy versus 56.79\% on complex molecules and 55.54\% versus 49.45\% on innovative reactions. Through detailed ablation studies and visualizations, we demonstrate how DAA generates interpretable attention patterns that adapt to different molecular contexts. Our approach represents a general framework for context-aware protein representation in biocatalysis prediction, with potential applications across enzymatic synthesis planning. We open-source our implementation and pre-trained models to facilitate further research.