arXiv subjects

Weiqiang Bai

Publications and source records attributed to Weiqiang Bai.

7 recordsLinked to original sources

arXiv2026

Structure-guided taxonomic placement of divergent RNA viruses with ViraClass

Metatranscriptomic sequencing has expanded our knowledge of the RNA virosphere far more rapidly than novel viruses can be taxonomically classified. Taxonomic assignment above the family level is particularly difficult because the RNA-dependent RNA polymerase (RdRp) is often the only gene retained across RNA viruses yet exhibits little sequence similarity among highly divergent viruses. Here we show that RdRp protein structure retains taxonomic signal at evolutionary depths where RdRp primary sequence similarity has largely collapsed, and that the organization of this signal is consistent with the current ICTV hierarchy. Based on this, we developed ViraClass, a hierarchical framework for RNA virus taxonomic placement that uses RdRp structure for rank-by-rank assignment from phylum to genus, stopping at the deepest rank supported by confidence thresholds, and calibrated structural clustering for viruses that remain outside existing reference space. Across random-split, prospective and taxonomic hold-out benchmarks, ViraClass outperforms sequence-based and genome-content baselines. The largest gains emerge at deep evolutionary distances, in benchmarks that withhold entire families, orders or classes from the reference, where sequence-based methods lose most of their signal. In challenging boundary cases such as the Flaviviridae, ViraClass's structure-based placements capture the taxonomic boundary tensions highlighted by recent phylogenetic studies. When applied to a large collection of previously unclassified RdRp sequences, ViraClass places high-confidence queries into existing phyla and organizes the remainder into compact structural groups. ViraClass therefore provides a scalable approach from large-scale virus discovery to hierarchical taxonomic interpretation, particularly at the deep evolutionary ranges that current sequence-based pipelines cannot reach.

q-bio.QM↗

arXiv2026

ViraHinter: a dual-modal artificial intelligence framework for predicting virus-host interactions

Protein-protein interactions (PPIs) between a virus and its host govern infection, replication, and pathogenesis. While high-throughput mapping has identified thousands of virus-host associations, much of the virus-host interactome remains uncharacterized due to the labor-intensive nature of experimental screens, the inherent difficulty in capturing transient interactions, and the limited sequence homology across divergent viral families. Here, we introduce ViraHinter, a dual-modal deep learning framework for the precise prediction of virus-host interactions and large-scale inference of interaction landscapes. ViraHinter couples a structure-generation branch with a sequence-representation branch, integrating structure-informed pair representations with ESM-derived embeddings to learn generalizable interaction rules across unseen viruses. We benchmark ViraHinter on pathogenic coronaviruses and influenza A viruses and show that it consistently outperforms RoseTTAFold2-PPI, AlphaFold 3 and RoseTTAFold2-Lite in prioritizing high-confidence candidates even under severe class imbalance and across diverse interface regimes. Notably, it successfully identifies novel functionally relevant host factors and recapitulates the structural plasticity of the complex interfaces. By intersecting predictions across multiple influenza subtypes, ViraHinter reveals 33 shared host factors, offering a roadmap for broad-spectrum antiviral discovery. ViraHinter therefore serves as a robust computational approach for studying virus-host interactions, enabling systematic screening of host factors for all known human-infecting viruses, providing new insights into the shared mechanisms of viral pathogenesis, and accelerating the discovery of novel therapeutic targets and the development of broad-spectrum antivirals.

q-bio.BM↗

arXiv2025

Fitness aligned structural modeling enables scalable virtual screening with AuroBind

Most human proteins remain undrugged, over 96% of human proteins remain unexploited by approved therapeutics. While structure-based virtual screening promises to expand the druggable proteome, existing methods lack atomic-level precision and fail to predict binding fitness, limiting translational impact. We present AuroBind, a scalable virtual screening framework that fine-tunes a custom atomic-level structural model on million-scale chemogenomic data. AuroBind integrates direct preference optimization, self-distillation from high-confidence complexes, and a teacher-student acceleration strategy to jointly predict ligand-bound structures and binding fitness. The proposed models outperform state-of-the-art models on structural and functional benchmarks while enabling 100,000-fold faster screening across ultra-large compound libraries. In a prospective screen across ten disease-relevant targets, AuroBind achieved experimental hit rates of 7-69%, with top compounds reaching sub-nanomolar to picomolar potency. For the orphan GPCRs GPR151 and GPR160, AuroBind identified both agonists and antagonists with success rates of 16-30%, and functional assays confirmed GPR160 modulation in liver and prostate cancer models. AuroBind offers a generalizable framework for structure-function learning and high-throughput molecular screening, bridging the gap between structure prediction and therapeutic discovery.

cs.LG↗

arXiv2025

Revisiting Convolution Architecture in the Realm of DNA Foundation Models

In recent years, a variety of methods based on Transformer and state space model (SSM) architectures have been proposed, advancing foundational DNA language models. However, there is a lack of comparison between these recent approaches and the classical architecture convolutional networks (CNNs) on foundation model benchmarks. This raises the question: are CNNs truly being surpassed by these recent approaches based on transformer and SSM architectures? In this paper, we develop a simple but well-designed CNN-based method termed ConvNova. ConvNova identifies and proposes three effective designs: 1) dilated convolutions, 2) gated convolutions, and 3) a dual-branch framework for gating mechanisms. Through extensive empirical experiments, we demonstrate that ConvNova significantly outperforms recent methods on more than half of the tasks across several foundation model benchmarks. For example, in histone-related tasks, ConvNova exceeds the second-best method by an average of 5.8%, while generally utilizing fewer parameters and enabling faster computation. In addition, the experiments observed findings that may be related to biological characteristics. This indicates that CNNs are still a strong competitor compared to Transformers and SSMs. We anticipate that this work will spark renewed interest in CNN-based methods for DNA foundation models.

cs.LG↗

arXiv2024

Model Decides How to Tokenize: Adaptive DNA Sequence Tokenization with MxDNA

Foundation models have made significant strides in understanding the genomic language of DNA sequences. However, previous models typically adopt the tokenization methods designed for natural language, which are unsuitable for DNA sequences due to their unique characteristics. In addition, the optimal approach to tokenize DNA remains largely under-explored, and may not be intuitively understood by humans even if discovered. To address these challenges, we introduce MxDNA, a novel framework where the model autonomously learns an effective DNA tokenization strategy through gradient decent. MxDNA employs a sparse Mixture of Convolution Experts coupled with a deformable convolution to model the tokenization process, with the discontinuous, overlapping, and ambiguous nature of meaningful genomic segments explicitly considered. On Nucleotide Transformer Benchmarks and Genomic Benchmarks, MxDNA demonstrates superior performance to existing methods with less pretraining data and time, highlighting its effectiveness. Finally, we show that MxDNA learns unique tokenization strategy distinct to those of previous methods and captures genomic functionalities at a token level during self-supervised pretraining. Our MxDNA aims to provide a new perspective on DNA tokenization, potentially offering broad applications in various domains and yielding profound insights.

q-bio.GN↗

arXiv2024

COMET: Benchmark for Comprehensive Biological Multi-omics Evaluation Tasks and Language Models

As key elements within the central dogma, DNA, RNA, and proteins play crucial roles in maintaining life by guaranteeing accurate genetic expression and implementation. Although research on these molecules has profoundly impacted fields like medicine, agriculture, and industry, the diversity of machine learning approaches-from traditional statistical methods to deep learning models and large language models-poses challenges for researchers in choosing the most suitable models for specific tasks, especially for cross-omics and multi-omics tasks due to the lack of comprehensive benchmarks. To address this, we introduce the first comprehensive multi-omics benchmark COMET (Benchmark for Biological COmprehensive Multi-omics Evaluation Tasks and Language Models), designed to evaluate models across single-omics, cross-omics, and multi-omics tasks. First, we curate and develop a diverse collection of downstream tasks and datasets covering key structural and functional aspects in DNA, RNA, and proteins, including tasks that span multiple omics levels. Then, we evaluate existing foundational language models for DNA, RNA, and proteins, as well as the newly proposed multi-omics method, offering valuable insights into their performance in integrating and analyzing data from different biological modalities. This benchmark aims to define critical issues in multi-omics research and guide future directions, ultimately promoting advancements in understanding biological processes through integrated and different omics data analysis.

q-bio.BM↗

arXiv2024

Toward Understanding BERT-Like Pre-Training for DNA Foundation Models

With the success of large-scale pre-training in language tasks, there is an increasing trend of applying it to the domain of life sciences. In particular, pre-training methods based on DNA sequences have received increasing attention because of their potential to capture general information about genes. However, existing pre-training methods for DNA sequences largely rely on direct adoptions of BERT pre-training from NLP, lacking a comprehensive understanding and a specifically tailored approach. To address this research gap, we provide the first empirical study with three insightful observations. Based on the empirical study, we notice that overlapping tokenizer can benefit the fine-tuning of downstream tasks but leads to inadequate pre-training with fast convergence. To unleash the pre-training potential, we introduce a novel approach called RandomMask, which gradually increases the task difficulty of BERT-like pre-training by continuously expanding its mask boundary, forcing the model to learn more knowledge. RandomMask is simple but effective, achieving state-of-the-art performance across 6 downstream tasks. RandomMask achieves a staggering 68.16\% in Matthew's correlation coefficient for Epigenetic Mark Prediction, a groundbreaking increase of 19.85\% over the baseline and a remarkable 3.69\% improvement over the previous state-of-the-art result.

cs.AI↗