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The advent of deep learning has introduced efficient approaches for de novo protein sequence design, significantly improving success rates and reducing development costs compared to computational or experimental methods. However, existing methods face challenges in generating proteins with diverse lengths and shapes while maintaining key structural features. To address these challenges, we introduce CPDiffusion-SS, a latent graph diffusion model that generates protein sequences based on coarse-grained secondary structural information. CPDiffusion-SS offers greater flexibility in producing a variety of novel amino acid sequences while preserving overall structural constraints, thus enhancing the reliability and diversity of generated proteins. Experimental analyses demonstrate the significant superiority of the proposed method in producing diverse and novel sequences, with CPDiffusion-SS surpassing popular baseline methods on open benchmarks across various quantitative measurements. Furthermore, we provide a series of case studies to highlight the biological significance of the generation performance by the proposed method. The source code is publicly available at https://github.com/riacd/CPDiffusion-SS, Comment: 10 pages, 4 figures

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., Comment: 8 pages, 4 figures

Fine-tuning Pre-trained protein language models (PLMs) has emerged as a prominent strategy for enhancing downstream prediction tasks, often outperforming traditional supervised learning approaches. As a widely applied powerful technique in natural language processing, employing Parameter-Efficient Fine-Tuning techniques could potentially enhance the performance of PLMs. However, the direct transfer to life science tasks is non-trivial due to the different training strategies and data forms. To address this gap, we introduce SES-Adapter, a simple, efficient, and scalable adapter method for enhancing the representation learning of PLMs. SES-Adapter incorporates PLM embeddings with structural sequence embeddings to create structure-aware representations. We show that the proposed method is compatible with different PLM architectures and across diverse tasks. Extensive evaluations are conducted on 2 types of folding structures with notable quality differences, 9 state-of-the-art baselines, and 9 benchmark datasets across distinct downstream tasks. Results show that compared to vanilla PLMs, SES-Adapter improves downstream task performance by a maximum of 11% and an average of 3%, with significantly accelerated training speed by a maximum of 1034% and an average of 362%, the convergence rate is also improved by approximately 2 times. Moreover, positive optimization is observed even with low-quality predicted structures. The source code for SES-Adapter is available at https://github.com/tyang816/SES-Adapter., Comment: 30 pages, 4 figures, 8 tables

Social networks represent a common form of interconnected data frequently depicted as graphs within the domain of deep learning-based inference. These communities inherently form dynamic systems, achieving stability through continuous internal communications and opinion exchanges among social actors along their social ties. In contrast, neural message passing in deep learning provides a clear and intuitive mathematical framework for understanding information propagation and aggregation among connected nodes in graphs. Node representations are dynamically updated by considering both the connectivity and status of neighboring nodes. This research harmonizes concepts from sociometry and neural message passing to analyze and infer the behavior of dynamic systems. Drawing inspiration from opinion dynamics in sociology, we propose ODNet, a novel message passing scheme incorporating bounded confidence, to refine the influence weight of local nodes for message propagation. We adjust the similarity cutoffs of bounded confidence and influence weights of ODNet and define opinion exchange rules that align with the characteristics of social network graphs. We show that ODNet enhances prediction performance across various graph types and alleviates oversmoothing issues. Furthermore, our approach surpasses conventional baselines in graph representation learning and proves its practical significance in analyzing real-world co-occurrence networks of metabolic genes. Remarkably, our method simplifies complex social network graphs solely by leveraging knowledge of interaction frequencies among entities within the system. It accurately identifies internal communities and the roles of genes in different metabolic pathways, including opinion leaders, bridge communicators, and isolators.

Designing protein mutants of both high stability and activity is a critical yet challenging task in protein engineering. Here, we introduce Pro-PRIME, a deep learning zero-shot model, which can suggest protein mutants of improved stability and activity without any prior experimental mutagenesis data. By leveraging temperature-guided language modelling, Pro-PRIME demonstrated superior predictive power compared to current state-of-the-art models on the public mutagenesis dataset over 33 proteins. Furthermore, we carried out wet experiments to test Pro-PRIME on five distinct proteins to engineer certain physicochemical properties, including thermal stability, rates of RNA polymerization and DNA cleavage, hydrolase activity, antigen-antibody binding affinity, or even the nonnatural properties, e.g., the ability to polymerize non-natural nucleic acid or resilience to extreme alkaline conditions. Surprisingly, about 40% AI-designed mutants show better performance than the one before mutation for all five proteins studied and for all properties targeted for engineering. Hence, Pro-PRIME demonstrates the general applicability in protein engineering., Comment: arXiv admin note: text overlap with arXiv:2304.03780

Prior works about text-to-image synthesis typically concatenated the sentence embedding with the noise vector, while the sentence embedding and the noise vector are two different factors, which control the different aspects of the generation. Simply concatenating them will entangle the latent factors and encumber the generative model. In this paper, we attempt to decompose these two factors and propose Factor Decomposed Generative Adversarial Networks~(FDGAN). To achieve this, we firstly generate images from the noise vector and then apply the sentence embedding in the normalization layer for both generator and discriminators. We also design an additive norm layer to align and fuse the text-image features. The experimental results show that decomposing the noise and the sentence embedding can disentangle latent factors in text-to-image synthesis, and make the generative model more efficient. Compared with the baseline, FDGAN can achieve better performance, while fewer parameters are used.

The wide deployment of speech-based biometric systems usually demands high-performance speaker recognition algorithms. However, most of the prior works for speaker recognition either process the speech in the frequency domain or time domain, which may produce suboptimal results because both time and frequency domains are important for speaker recognition. In this paper, we attempt to analyze the speech signal in both time and frequency domains and propose the time-frequency network~(TFN) for speaker recognition by extracting and fusing the features in the two domains. Based on the recent advance of deep neural networks, we propose a convolution neural network to encode the raw speech waveform and the frequency spectrum into domain-specific features, which are then fused and transformed into a classification feature space for speaker recognition. Experimental results on the publicly available datasets TIMIT and LibriSpeech show that our framework is effective to combine the information in the two domains and performs better than the state-of-the-art methods for speaker recognition., Comment: 5pages, 3 figures

Gonadotrophin-releasing hormone receptor (GnRH1R) is a promising therapeutic target for the treatment of uterine diseases. To date, several GnRH1R antagonists are available in clinical investigation without satisfying multiple property constraints. To fill this gap, we aim to develop a deep learning-based framework to facilitate the effective and efficient discovery of a new orally active small-molecule drug targeting GnRH1R with desirable properties. In the present work, a ligand-and-structure combined model, namely LS-MolGen, was firstly proposed for molecular generation by fully utilizing the information on the known active compounds and the structure of the target protein, which was demonstrated by its superior performance than ligand- or structure-based methods separately. Then, a in silico screening including activity prediction, ADMET evaluation, molecular docking and FEP calculation was conducted, where ~30,000 generated novel molecules were narrowed down to 8 for experimental synthesis and validation. In vitro and in vivo experiments showed that three of them exhibited potent inhibition activities (compound 5 IC50 = 0.856 nM, compound 6 IC50 = 0.901 nM, compound 7 IC50 = 2.54 nM) against GnRH1R, and compound 5 performed well in fundamental PK properties, such as half-life, oral bioavailability, and PPB, etc. We believed that the proposed ligand-and-structure combined molecular generative model and the whole computer-aided workflow can potentially be extended to similar tasks for de novo drug design or lead optimization.

X-ray absorption spectroscopy (XAS) is an indispensable tool to characterize the atomic-scale three-dimensional local structure of the system, in which XANES is the most important energy region to reflect the three-dimensional structure. However quantitative analysis of three-dimensional structure from XANES requires users to have a deep understanding and accurate judgment of structural information and summarize several structural parameters, which is often difficult to achieve. In this work, We construct \textbf{physics-informed Graph neural network} and \textbf{Transformer} models for calculating XANES from the input three-dimensional structure; we improve the efficiency of the model based on the physical meaning of XAS; then we combine the model and optimization algorithm to fit the three-dimensional structure of given system. This method does not require users to summarize the structural parameters, has wide application range. It can be applied to the three-dimensional structure analysis of solid materials and has positive significance for the study of structure-function relationship in the fields of energy and catalysis. In addition, this method is expected to be developed into an online three-dimensional structure analysis method for XAS related beamlines.