Immunogenicity prediction is a central topic in reverse vaccinology for finding candidate vaccines that can trigger protective immune responses. Existing approaches typically rely on highly compressed features and simple model architectures, leading to limited prediction accuracy and poor generalizability. To address these challenges, we introduce VenusVaccine, a novel deep learning solution with a dual attention mechanism that integrates pre-trained latent vector representations of protein sequences and structures. We also compile the most comprehensive immunogenicity dataset to date, encompassing over 7000 antigen sequences, structures, and immunogenicity labels from bacteria, viruses, and tumors. Extensive experiments demonstrate that VenusVaccine outperforms existing methods across a wide range of evaluation metrics. Furthermore, we establish a post-hoc validation protocol to assess the practical significance of deep learning models in tackling vaccine design challenges. Our work provides an effective tool for vaccine design and sets valuable benchmarks for future research. The implementation is at \url{https://github.com/songleee/VenusVaccine}.

MOTIVATION: Enzyme engineering is a critical approach for producing enzymes that meet industrial and research demands by modifying wild-type proteins to enhance properties such as catalytic activity and thermostability. Beyond traditional directed evolution and rational design, recent advancements in deep learning offer cost-effective and high-performance alternatives. By encoding implicit coevolutionary patterns, these pretrained models have become powerful tools, with the central challenge being to uncover the intricate relationships among protein sequence, structure, and function. RESULTS: We present VenusREM, a retrieval-enhanced protein language model designed to capture local amino acid interactions in both spatial and temporal scales. VenusREM achieves state-of-the-art performance on 217 assays from the ProteinGym benchmark. Beyond high-throughput open benchmark validations, we conducted a low-throughput post hoc analysis on more than 30 mutants to verify the model's ability to improve the stability and binding affinity of a VHH antibody. We also validated the effectiveness of VenusREM by designing 10 novel mutants of a DNA polymerase and performing wet-lab experiments to evaluate their enhanced activity at elevated temperatures. Both in silico and experimental evaluations not only confirm the reliability of VenusREM as a computational tool for enzyme engineering but also demonstrate a comprehensive evaluation framework for future computational studies in mutation effect prediction. AVAILABILITY AND IMPLEMENTATION: The implementation is available at https://github.com/tyang816/VenusREM.

MOTIVATION: A pivotal area of research in antibody engineering is to find effective modifications that enhance antibody-antigen binding affinity. Traditional wet-lab experiments assess mutants in a costly and time-consuming manner. Emerging deep learning solutions offer an alternative by modeling antibody structures to predict binding affinity changes. However, they heavily depend on high-quality complex structures, which are frequently unavailable in practice. Therefore, we propose ProtAttBA, a deep learning model that predicts binding affinity changes based solely on the sequence information of antibody-antigen complexes. RESULTS: ProtAttBA employs a pre-training phase to learn protein sequence patterns, following a supervised training phase using labeled antibody-antigen complex data to train a cross-attention-based regressor for predicting binding affinity changes. We evaluated ProtAttBA on three open benchmarks under different conditions. Compared to both sequence- and structure-based prediction methods, our approach achieves competitive performance, demonstrating notable robustness, especially with uncertain complex structures. Notably, our method possesses interpretability from the attention mechanism. We show that the learned attention scores can identify critical residues with impacts on binding affinity. This work introduces a rapid and cost-effective computational tool for antibody engineering, with the potential to accelerate the development of novel therapeutic antibodies. AVAILABILITY AND IMPLEMENTATION: Source codes and data are available at https://github.com/code4luck/ProtAttBA.

Designing protein sequences with restrictions or conditions is an important research topic in biology. Many powerful deep generative models have been proposed to create proteins belonging to specific families or with determined backbone structures. However, the amount of homologous data is not always sufficient for any proteins to train a model, and proteins from the same family may lack the necessary structural similarity, posing challenges in ensuring the presence of crucial structures in the generated proteins. On the other hand, when generating proteins with fixed backbone, there exists a trade-off between reliability and flexibility of sequence generation, necessitating prior specification of protein length and precise positions of amino acids. This work introduces a flexible protein generation method for amino acid sequence generation with latent diffusion models and protein language models. The generation is conditioned on protein secondary structures to address the practical considerations in bioengineering better. It enables the imposition of structural constraints on generated proteins while ensuring an adequate level of novelty and diversity at the sequence level. We compare the performance of our method against popular language models and structure-based methods using quantifiable metrics, demonstrating its superiority in generating diverse and novel sequences that exhibit high foldability. Furthermore, we provide case studies of generating proteins with specific secondary structures to analyze the biological significance of our method. The source code is publicly available at https://github.com/riacd/CPDiffusion-SS.

Deep learning has become a crucial tool in studying proteins. While the significance of modeling protein structure has been discussed extensively in the literature, amino acid types are typically included in the input as a default operation for many inference tasks. This study demonstrates with structure alignment task that embedding amino acid types in some cases may not help a deep learning model learn better representation. To this end, we propose ProtLOCA, a local geometry alignment method based solely on amino acid structure representation. The effectiveness of ProtLOCA is examined by a global structure-matching task on protein pairs with an independent test dataset based on CATH labels. Our method outperforms existing sequence-and structure-based representation learning methods by more quickly and accurately matching structurally consistent protein domains. Furthermore, in local structure pairing tasks, ProtLOCA for the first time provides a valid solution to highlight common local structures among proteins with different overall structures but the same function. This suggests a new possibility for using deep learning methods to analyze protein structure to infer function.

Protein language models (PLMs) have shown remarkable capabilities in various protein function prediction tasks. However, while protein function is intricately tied to structure, most existing PLMs do not incorporate protein structure information. To address this issue, we introduce ProSST, a Transformer-based protein language model that seamlessly integrates both protein sequences and structures. ProSST incorporates a structure quantization module and a Transformer architecture with disentangled attention. The structure quantization module translates a 3D protein structure into a sequence of discrete tokens by first serializing the protein structure into residue-level local structures and then embeds them into dense vector space. These vectors are then quantized into discrete structure tokens by a pre-trained clustering model. These tokens serve as an effective protein structure representation. Furthermore, ProSST explicitly learns the relationship between protein residue token sequences and structure token sequences through the sequence-structure disentangled attention. We pre-train ProSST on millions of protein structures using a masked language model objective, enabling it to learn comprehensive contextual representations of proteins. To evaluate the proposed ProSST, we conduct extensive experiments on the zero-shot mutation effect prediction and several supervised downstream tasks, where ProSST achieves the state-of-the-art performance among all baselines. Our code and pre-trained models are publicly available.

Graph data collected from the real world often contains noise, making it imperative to develop robust representation learning tools for graphs. While existing research has primarily focused on feature smoothing, the robustness of the underlying geometric structure is frequently overlooked. In addition, the prevalent use of the$\mathbb {L}_{2}$-norm for achieving global smoothness in graph neural networks shrinks many local characteristics, limiting their expressivity on a node's neighboring information. This paper introduces novel regularizers designed to address noise in both feature and structural aspects of graph data. We employ the alternating direction method of multipliers (ADMM) to optimize the objective function. Our proposed approach effectively prevents oversmoothing graph signal representations when applying multiple layers and ensures convergence to optimal solutions. Empirical results from our study demonstrate the superior performance of our proposedDoTover popular graph convolutions, especially in scenarios where the graph is heavily contaminated.

The metric learning paradigm has achieved notable success in few-shot action recognition; however, it faces unaddressed challenges. Specifically,(1)limited training data could impede the exploration of temporal action relations, and(2)precision would decline from the presence of outliers during the frame-level feature alignment. To address the challenges, we propose a two-stream temporal feature aggregation method based on clustering, incorporating a temporal augmentation module (TAM) and a feature aggregation module (FAM). The TAM adeptly integrates three consecutive grayscale frames into the original RGB frame through weighted summation, thereby addressing the color-related misguidance and enhancing the temporal information extraction. Meanwhile, the FAM employs clustering to aggregate the frame-level features into high semantic sub-actions and replaces the original features with cluster centers to mitigate the adverse impact of outliers on the model performance. Experimental results on benchmark datasets demonstrate the effectiveness of our method in few-shot action recognition. We validate our proposed approach by conducting comprehensive ablation experiments.

Gigapixel medical images are a rich source of information containing both morphological textures and spatial information. However, existing deep learning solutions primarily rely on convolutional neural networks (CNNs) for global pixel-level analysis, ignoring the underlying local geometric structure. Since the topological structure in medical images is closely related to tumor evolution, graphs can be utilized to characterize it. To obtain a more comprehensive representation for downstream analysis, a fusion framework is proposed to enhance the global image-level representation captured by CNNs with the geometry of cell-level spatial information learned by graph neural networks (GNN). Two fusion strategies have been developed: one with MLP, which is simple but efficient through fine-tuning, and the other with TRANSFORMER, which excels in fusing multiple networks. The proposed fusion strategies have been evaluated on histology datasets from large patient cohorts of colorectal and gastric cancers for three biomarker prediction tasks. Both models outperform plain CNNs or GNNs, achieving a consistent AUC improvement of more than 5% on various network backbones. Importantly, the experimental results demonstrate the necessity of combining image-level morphological features with cell spatial relations in medical image analysis. Codes are available at https://github.com/yiqings/HEGnnEnhanceCnn.

Inverse protein folding is challenging due to its inherent one-to-many mapping characteristic, where numerous possible amino acid sequences can fold into a single, identical protein backbone. This task involves not only identifying viable sequences but also representing the sheer diversity of potential solutions. However, existing discriminative models, such as transformer-based auto-regressive models, struggle to encapsulate the diverse range of plausible solutions. In contrast, diffusion probabilistic models, as an emerging genre of generative approaches, offer the potential to generate a diverse set of sequence candidates for determined protein backbones. We propose a novel graph denoising diffusion model for inverse protein folding, where a given protein backbone guides the diffusion process on the corresponding amino acid residue types. The model infers the joint distribution of amino acids conditioned on the nodes' physiochemical properties and local environment. Moreover, we utilize amino acid replacement matrices for the diffusion forward process, encoding the biologically-meaningful prior knowledge of amino acids from their spatial and sequential neighbors as well as themselves, which reduces the sampling space of the generative process. Our model achieves state-of-the-art performance over a set of popular baseline methods in sequence recovery and exhibits great potential in generating diverse protein sequences for a determined protein backbone structure.

The performance of graph representation learning is affected by the quality of graph input. While existing research usually pursues a globally smoothed graph embedding, we believe the rarely observed anomalies are as well harmful to an accurate prediction. This work establishes a graph learning scheme that automatically detects (locally) corrupted feature attributes and recovers robust embedding for prediction tasks. The detection operation leverages a graph autoencoder, which does not make any assumptions about the distribution of the local corruptions. It pinpoints the positions of the anomalous node attributes in an unbiased mask matrix, where robust estimations are recovered with sparsity promoting regularizer. The optimizer approaches a new embedding that is sparse in the framelet domain and conditionally close to input observations. Extensive experiments are provided to validate our proposed model can recover a robust graph representation from black-box poisoning and achieve excellent performance.

Graph representation learning has many real-world applications, from self-driving LiDAR, 3D computer vision to drug repurposing, protein classification, social networks analysis. An adequate representation of graph data is vital to the learning performance of a statistical or machine learning model for graph-structured data. This paper proposes a novel multiscale representation system for graph data, called decimated framelets, which form a localized tight frame on the graph. The decimated framelet system allows storage of the graph data representation on a coarse-grained chain and processes the graph data at multi scales where at each scale, the data is stored on a subgraph. Based on this, we establish decimated G-framelet transforms for the decomposition and reconstruction of the graph data at multi resolutions via a constructive data-driven filter bank. The graph framelets are built on a chain-based orthonormal basis that supports fast graph Fourier transforms. From this, we give a fast algorithm for the decimated G-framelet transforms, or FGT, that has linear computational complexity O(N) for a graph of size N. The effectiveness for constructing the decimated framelet system and the FGT is demonstrated by a simulated example of random graphs and real-world applications, including multiresolution analysis for traffic network and representation learning of graph neural networks for graph classification tasks.

This paper presents a new approach for assembling graph neural networks based on framelet transforms. The latter provides a multi-scale representation for graph-structured data. We decompose an input graph into low-pass and high-pass frequencies coefficients for network training, which then defines a framelet-based graph convolution. The framelet decomposition naturally induces a graph pooling strategy by aggregating the graph feature into low-pass and high-pass spectra, which considers both the feature values and geometry of the graph data and conserves the total information. The graph neural networks with the proposed framelet convolution and pooling achieve state-of-the-art performance in many node and graph prediction tasks. Moreover, we propose shrinkage as a new activation for the framelet convolution, which thresholds high-frequency information at different scales. Compared to ReLU, shrinkage activation improves model performance on denoising and signal compression: noises in both node and structure can be significantly reduced by accurately cutting off the high-pass coefficients from framelet decomposition, and the signal can be compressed to less than half its original size with well-preserved prediction performance.

Adam-type optimizers, as a class of adaptive moment estimation methods with the exponential moving average scheme, have been successfully used in many applications of deep learning. Such methods are appealing due to the capability on large-scale sparse datasets with high computational efficiency. In this paper, we present a new framework for Adam-type methods with the trend information when updating the parameters with the adaptive step size and gradients. The additional terms in the algorithm promise an efficient movement on the complex cost surface, and thus the loss would converge more rapidly. We show empirically the importance of adding the trend component, where our framework outperforms the conventional Adam and AMSGrad methods constantly on the classical models with several real-world datasets.