Therapeutic peptides show promise in targeting previously undruggable binding sites, with recent advancements in deep generative models enabling full-atom peptide co-design for specific protein receptors.However, the critical role of molecular surfaces in proteinprotein interactions (PPIs) has been underexplored.To bridge this gap, we propose an omni-design peptides generation paradigm, called SurfFlow, a novel surface-based generative algorithm that enables comprehensive co-design of sequence, structure, and surface for peptides.SurfFlow employs a multi-modality conditional flow matching (CFM) architecture to learn distributions of surface geometries and biochemical properties, enhancing peptide binding accuracy.Evaluated on the comprehensive PepMerge benchmark, SurfFlow consistently outperforms full-atom baselines across all metrics.These results highlight the advantages of considering molecular surfaces in de novo peptide discovery and demonstrate the potential of integrating multiple protein modalities for more effective therapeutic peptide discovery.

Molecular interaction prediction plays a crucial role in forecasting unknown interactions between molecules, such as drug-target interaction (DTI) and drug-drug interaction (DDI), which are essential in the field of drug discovery and therapeutics. Although previous prediction methods have yielded promising results by leveraging the rich semantics and topological structure of biomedical knowledge graphs (KGs), they have primarily focused on enhancing predictive performance without addressing the presence of inevitable noise and inconsistent semantics. This limitation has hindered the advancement of KG-based prediction methods. To address this limitation, we propose BioKDN (BiomedicalKnowledge GraphDenoisingNetwork) for robust molecular interaction prediction. BioKDN refines the reliable structure of local subgraphs by denoising noisy links in a learnable manner, providing a general module for extracting task-relevant interactions. To enhance the reliability of the refined structure, BioKDN maintains consistent and robust semantics by smoothing relations around the target interaction. By maximizing the mutual information between reliable structure and smoothed relations, BioKDN emphasizes informative semantics to enable precise predictions. Experimental results on real-world datasets show that BioKDN surpasses state-of-the-art models in DTI and DDI prediction tasks, confirming the effectiveness and robustness of BioKDN in denoising unreliable interactions within contaminated KGs.

Molecular interaction prediction is essential in various applications including drug discovery and material science. The problem becomes quite challenging when the interaction is represented by unmapped relationships in molecular networks, namely molecular interaction, because it easily suffers from (i) insufficient labeled data with many false-positive samples, and (ii) ignoring a large number of biological entities with rich information in the knowledge graph. Most of the existing methods cannot properly exploit the information of knowledge graph and molecule graph simultaneously. In this paper, we propose a large-scaleKnowledgeGraph enhancedMulti-TaskLearning model, namely KG-MTL, which extracts the features from both knowledge graph and molecular graph in a synergistic way. Moreover, we design an effectiveShared Unitthat helps the model to jointly preserve the semantic relations of drug entity and the neighbor structures of the compound in both knowledge graph and molecular graph. Extensive experiments on four real-world datasets demonstrate that our proposed KG-MTL outperforms the state-of-the-art methods on two representative molecular interaction prediction tasks: drug-target interaction prediction and compound-protein interaction prediction. The source code of KG-MTL is available athttps://github.com/xzenglab/KG-MTL.

NN-Descent is a classic k-NN graph construction approach. It is still widely employed in machine learning, computer vision, and information retrieval tasks due to its efficiency and genericness. However, the current design only works well on CPU. In this paper, NN-Descent has been redesigned to adapt to the GPU architecture. A new graph update strategy called selective update is proposed. It reduces the data exchange between GPU cores and GPU global memory significantly, which is the processing bottleneck under GPU computation architecture. This redesign leads to full exploitation of the parallelism of the GPU hardware. In the meantime, the genericness, as well as the simplicity of NN-Descent, are well-preserved. Moreover, a procedure that allows to k-NN graph to be merged efficiently on GPU is proposed. It makes the construction of high-quality k-NN graphs for out-of-GPU-memory datasets tractable. Our approach is 100-250× faster than the single-thread NN-Descent and is 2.5-5× faster than the existing GPU-based approaches as we tested on million as well as billion scale datasets.