arXiv subjects

Mutian He

Publications and source records attributed to Mutian He.

16 recordsLinked to original sources

arXiv2026

Is Retrieval All You Need? Assessment and Emergence of Novelty in Protein Structure Generation

Protein backbone generation models are often credited with exploring novel fold space based solely on low full-chain similarity to known proteins, yet this cannot distinguish a genuinely new fold from a novel assembly of known structural units. We first ask whether this granularity mismatch alone explains the reported rates, and introduce the Domain Retrieval Rate (DRR), the fraction of generated backbones for which any constituent domain matches a known domain in CATH S40. Applied to eight backbone generation models spanning diffusion and flow-matching paradigms, DRR finds locally alignable known structure in most outputs, while the fraction containing a substantially covered complete domain is considerably smaller and depends on the scoring convention. To calibrate what retrieval alone can achieve, we propose RetFold, a zero-training baseline that constructs backbones by retrieving CATH domains and refining inter-domain connections through geometry-based helix-linker optimization, at two orders of magnitude lower cost on CPU alone.

q-bio.BM↗

arXiv2026

CA-DEL: An Open Multi-Target, Multi-Modal Benchmark for Learning from DNA-Encoded Library Screens

The success of machine learning in drug discovery hinges on learning the relationship between a chemical structure and its biological activity. While DNA-Encoded Library (DEL) technology can generate the massive datasets required for this task, its primary signal -- sequencing read counts -- is an indirect and often noisy proxy for true molecular binding affinity. To address the scarcity of public benchmarks for developing robust models that can overcome this data challenge, we introduce CA-DEL, a multi-dimensional public benchmark featuring screens against three homologous carbonic anhydrase isoforms. While recent benchmarks like KinDEL have introduced 3D poses for kinase targets, CA-DEL distinguishes itself by focusing on the selectivity challenge among homologous Carbonic Anhydrase isoforms (CAII, CAIX, CAXII). Unlike benchmarks relying solely on noisy enrichment scores, CA-DEL integrates a rigorous validation set of experimentally determined binding affinities ($K_i$) from ChEMBL, establishing a critical Sim-to-Real evaluation paradigm: training on noisy DEL screens and testing on high-fidelity biophysical data.

q-bio.BM↗

arXiv2026

Bi-TEAM: A Unified Cross-Scale Representation Learning Framework for Chemically Modified Biomolecules

Representation learning for protein biochemical space faces a difficult trade-off: protein language models excel at capturing long-range biological semantics but often miss fine-grained chemical details. Conversely, chemical language models encode atomic information but lack broader sequence context. To address this, we introduce Bi-TEAM (Bi-gated Residual Space Modification), a general framework that injects localized chemical variation into global protein contexts. By ensuring robustness against perturbations such as non-canonical amino acids, post-translational modifications (PTMs), and topological constraints, Bi-TEAM uncovers functional chemical dependencies often missed by evolutionary baselines. Mechanistically, Bi-TEAM maps non-canonical residues to their natural counterparts and injects atomic-level data via a bi-gated residual fusion mechanism. Crucially, this process uses modification-aware prompts to ensure that local structural changes influence global functional representations without requiring alphabet expansion. We evaluated Bi-TEAM on ten datasets spanning chemically modified peptides, PTMs, and natural proteins. The model consistently outperformed state-of-the-art baselines, achieving up to a 66 percent improvement in Matthews correlation coefficient (MCC) on scaffold-similarity splits and a 350 percent increase in hemolysis prediction accuracy. Furthermore, when deployed as an oracle for generative modeling, Bi-TEAM nearly quadrupled the success rate for designing cell-penetrating cyclic peptides. By unifying biological semantics with chemical precision, Bi-TEAM provides a versatile foundation for machine learning driven exploration of peptide and protein biochemical space.

q-bio.BM↗

arXiv2025

CONFIDE: Hallucination Assessment for Reliable Biomolecular Structure Prediction and Design

Reliable evaluation of protein structure predictions remains challenging, as metrics like pLDDT capture energetic stability but often miss subtle errors such as atomic clashes or conformational traps reflecting topological frustration within the protein folding energy landscape. We present CODE (Chain of Diffusion Embeddings), a self evaluating metric empirically found to quantify topological frustration directly from the latent diffusion embeddings of the AlphaFold3 series of structure predictors in a fully unsupervised manner. Integrating this with pLDDT, we propose CONFIDE, a unified evaluation framework that combines energetic and topological perspectives to improve the reliability of AlphaFold3 and related models. CODE strongly correlates with protein folding rates driven by topological frustration, achieving a correlation of 0.82 compared to pLDDT's 0.33 (a relative improvement of 148\%). CONFIDE significantly enhances the reliability of quality evaluation in molecular glue structure prediction benchmarks, achieving a Spearman correlation of 0.73 with RMSD, compared to pLDDT's correlation of 0.42, a relative improvement of 73.8\%. Beyond quality assessment, our approach applies to diverse drug design tasks, including all-atom binder design, enzymatic active site mapping, mutation induced binding affinity prediction, nucleic acid aptamer screening, and flexible protein modeling. By combining data driven embeddings with theoretical insight, CODE and CONFIDE outperform existing metrics across a wide range of biomolecular systems, offering robust and versatile tools to refine structure predictions, advance structural biology, and accelerate drug discovery.

q-bio.BM↗

arXiv2025

Alleviating Forgetfulness of Linear Attention by Hybrid Sparse Attention and Contextualized Learnable Token Eviction

Linear-attention models that compress the entire input sequence into a fixed-size recurrent state offer an efficient alternative to Transformers, but their finite memory induces forgetfulness that harms retrieval-intensive tasks. To mitigate the issue, we explore a series of hybrid models that restore direct access to past tokens. We interleave token mixers with intermediate time and space complexity between linear and full attention, including sparse attention with token eviction, and the query-aware native sparse attention. Particularly, we propose a novel learnable token eviction approach. Combined with sliding-window attention, an end-to-end trainable lightweight CNN aggregates information from both past and future adjacent tokens to adaptively retain a limited set of critical KV-pairs per head, maintaining linear attention's constant time and space complexity. Efficient Triton kernels for the sparse attention mechanisms are provided. Empirical evaluations on retrieval-intensive benchmarks support the effectiveness of our approaches.

cs.CL↗

arXiv2024

DEL-Ranking: Ranking-Correction Denoising Framework for Elucidating Molecular Affinities in DNA-Encoded Libraries

DNA-encoded library (DEL) screening has revolutionized the detection of protein-ligand interactions through read counts, enabling rapid exploration of vast chemical spaces. However, noise in read counts, stemming from nonspecific interactions, can mislead this exploration process. We present DEL-Ranking, a novel distribution-correction denoising framework that addresses these challenges. Our approach introduces two key innovations: (1) a novel ranking loss that rectifies relative magnitude relationships between read counts, enabling the learning of causal features determining activity levels, and (2) an iterative algorithm employing self-training and consistency loss to establish model coherence between activity label and read count predictions. Furthermore, we contribute three new DEL screening datasets, the first to comprehensively include multi-dimensional molecular representations, protein-ligand enrichment values, and their activity labels. These datasets mitigate data scarcity issues in AI-driven DEL screening research. Rigorous evaluation on diverse DEL datasets demonstrates DEL-Ranking's superior performance across multiple correlation metrics, with significant improvements in binding affinity prediction accuracy. Our model exhibits zero-shot generalization ability across different protein targets and successfully identifies potential motifs determining compound binding affinity. This work advances DEL screening analysis and provides valuable resources for future research in this area.

cs.LG↗

arXiv2024

Joint Fine-tuning and Conversion of Pretrained Speech and Language Models towards Linear Complexity

Architectures such as Linformer and Mamba have recently emerged as competitive linear time replacements for transformers. However, corresponding large pretrained models are often unavailable, especially in non-text domains. To remedy this, we present a Cross-Architecture Layerwise Distillation (CALD) approach that jointly converts a transformer model to a linear time substitute and fine-tunes it to a target task. We also compare several means to guide the fine-tuning to optimally retain the desired inference capability from the original model. The methods differ in their use of the target model and the trajectory of the parameters. In a series of empirical studies on language processing, language modeling, and speech processing, we show that CALD can effectively recover the result of the original model, and that the guiding strategy contributes to the result. Some reasons for the variation are suggested.

cs.CL↗

arXiv2024

Unlocking Potential Binders: Multimodal Pretraining DEL-Fusion for Denoising DNA-Encoded Libraries

In the realm of drug discovery, DNA-encoded library (DEL) screening technology has emerged as an efficient method for identifying high-affinity compounds. However, DEL screening faces a significant challenge: noise arising from nonspecific interactions within complex biological systems. Neural networks trained on DEL libraries have been employed to extract compound features, aiming to denoise the data and uncover potential binders to the desired therapeutic target. Nevertheless, the inherent structure of DEL, constrained by the limited diversity of building blocks, impacts the performance of compound encoders. Moreover, existing methods only capture compound features at a single level, further limiting the effectiveness of the denoising strategy. To mitigate these issues, we propose a Multimodal Pretraining DEL-Fusion model (MPDF) that enhances encoder capabilities through pretraining and integrates compound features across various scales. We develop pretraining tasks applying contrastive objectives between different compound representations and their text descriptions, enhancing the compound encoders' ability to acquire generic features. Furthermore, we propose a novel DEL-fusion framework that amalgamates compound information at the atomic, submolecular, and molecular levels, as captured by various compound encoders. The synergy of these innovations equips MPDF with enriched, multi-scale features, enabling comprehensive downstream denoising. Evaluated on three DEL datasets, MPDF demonstrates superior performance in data processing and analysis for validation tasks. Notably, MPDF offers novel insights into identifying high-affinity molecules, paving the way for improved DEL utility in drug discovery.

q-bio.QM↗

arXiv2023

Can ChatGPT Detect Intent? Evaluating Large Language Models for Spoken Language Understanding

Recently, large pretrained language models have demonstrated strong language understanding capabilities. This is particularly reflected in their zero-shot and in-context learning abilities on downstream tasks through prompting. To assess their impact on spoken language understanding (SLU), we evaluate several such models like ChatGPT and OPT of different sizes on multiple benchmarks. We verify the emergent ability unique to the largest models as they can reach intent classification accuracy close to that of supervised models with zero or few shots on various languages given oracle transcripts. By contrast, the results for smaller models fitting a single GPU fall far behind. We note that the error cases often arise from the annotation scheme of the dataset; responses from ChatGPT are still reasonable. We show, however, that the model is worse at slot filling, and its performance is sensitive to ASR errors, suggesting serious challenges for the application of those textual models on SLU.

cs.CL↗

arXiv2023

The Interpreter Understands Your Meaning: End-to-end Spoken Language Understanding Aided by Speech Translation

End-to-end spoken language understanding (SLU) remains elusive even with current large pretrained language models on text and speech, especially in multilingual cases. Machine translation has been established as a powerful pretraining objective on text as it enables the model to capture high-level semantics of the input utterance and associations between different languages, which is desired for speech models that work on lower-level acoustic frames. Motivated particularly by the task of cross-lingual SLU, we demonstrate that the task of speech translation (ST) is a good means of pretraining speech models for end-to-end SLU on both intra- and cross-lingual scenarios. By introducing ST, our models reach higher performance over baselines on monolingual and multilingual intent classification as well as spoken question answering using SLURP, MINDS-14, and NMSQA benchmarks. To verify the effectiveness of our methods, we also create new benchmark datasets from both synthetic and real sources, for speech summarization and low-resource/zero-shot transfer from English to French or Spanish. We further show the value of preserving knowledge for the ST pretraining task for better downstream performance, possibly using Bayesian transfer regularizers.

cs.CL↗

arXiv2022

Acquiring and Modelling Abstract Commonsense Knowledge via Conceptualization

Conceptualization, or viewing entities and situations as instances of abstract concepts in mind and making inferences based on that, is a vital component in human intelligence for commonsense reasoning. Despite recent progress in artificial intelligence to acquire and model commonsense attributed to neural language models and commonsense knowledge graphs (CKGs), conceptualization is yet to be introduced thoroughly, making current approaches ineffective to cover knowledge about countless diverse entities and situations in the real world. To address the problem, we thoroughly study the role of conceptualization in commonsense reasoning, and formulate a framework to replicate human conceptual induction by acquiring abstract knowledge about events regarding abstract concepts, as well as higher-level triples or inferences upon them. We then apply the framework to ATOMIC, a large-scale human-annotated CKG, aided by the taxonomy Probase. We annotate a dataset on the validity of contextualized conceptualizations from ATOMIC on both event and triple levels, develop a series of heuristic rules based on linguistic features, and train a set of neural models to generate and verify abstract knowledge. Based on these components, a pipeline to acquire abstract knowledge is built. A large abstract CKG upon ATOMIC is then induced, ready to be instantiated to infer about unseen entities or situations. Finally, we empirically show the benefits of augmenting CKGs with abstract knowledge in downstream tasks like commonsense inference and zero-shot commonsense QA.

cs.CL↗

arXiv2021

Neural Lexicon Reader: Reduce Pronunciation Errors in End-to-end TTS by Leveraging External Textual Knowledge

End-to-end TTS requires a large amount of speech/text paired data to cover all necessary knowledge, particularly how to pronounce different words in diverse contexts, so that a neural model may learn such knowledge accordingly. But in real applications, such high demand of training data is hard to be satisfied and additional knowledge often needs to be injected manually. For example, to capture pronunciation knowledge on languages without regular orthography, a complicated grapheme-to-phoneme pipeline needs to be built based on a large structured pronunciation lexicon, leading to extra, sometimes high, costs to extend neural TTS to such languages. In this paper, we propose a framework to learn to automatically extract knowledge from unstructured external resources using a novel Token2Knowledge attention module. The framework is applied to build a TTS model named Neural Lexicon Reader that extracts pronunciations from raw lexicon texts in an end-to-end manner. Experiments show the proposed model significantly reduces pronunciation errors in low-resource, end-to-end Chinese TTS, and the lexicon-reading capability can be transferred to other languages with a smaller amount of data.

cs.SD↗

arXiv2021

Multilingual Byte2Speech Models for Scalable Low-resource Speech Synthesis

To scale neural speech synthesis to various real-world languages, we present a multilingual end-to-end framework that maps byte inputs to spectrograms, thus allowing arbitrary input scripts. Besides strong results on 40+ languages, the framework demonstrates capabilities to adapt to new languages under extreme low-resource and even few-shot scenarios of merely 40s transcribed recording, without the need of per-language resources like lexicon, extra corpus, auxiliary models, or linguistic expertise, thus ensuring scalability. While it retains satisfactory intelligibility and naturalness matching rich-resource models. Exhaustive comparative and ablation studies are performed to reveal the potential of the framework for low-resource languages. Furthermore, we propose a novel method to extract language-specific sub-networks in a multilingual model for a better understanding of its mechanism.

cs.CL↗

arXiv2020

On the Role of Conceptualization in Commonsense Knowledge Graph Construction

Commonsense knowledge graphs (CKGs) like Atomic and ASER are substantially different from conventional KGs as they consist of much larger number of nodes formed by loosely-structured text, which, though, enables them to handle highly diverse queries in natural language related to commonsense, leads to unique challenges for automatic KG construction methods. Besides identifying relations absent from the KG between nodes, such methods are also expected to explore absent nodes represented by text, in which different real-world things, or entities, may appear. To deal with the innumerable entities involved with commonsense in the real world, we introduce to CKG construction methods conceptualization, i.e., to view entities mentioned in text as instances of specific concepts or vice versa. We build synthetic triples by conceptualization, and further formulate the task as triple classification, handled by a discriminatory model with knowledge transferred from pretrained language models and fine-tuned by negative sampling. Experiments demonstrate that our methods can effectively identify plausible triples and expand the KG by triples of both new nodes and edges of high diversity and novelty.

cs.CL↗

arXiv2019

Neural Subgraph Isomorphism Counting

In this paper, we study a new graph learning problem: learning to count subgraph isomorphisms. Different from other traditional graph learning problems such as node classification and link prediction, subgraph isomorphism counting is NP-complete and requires more global inference to oversee the whole graph. To make it scalable for large-scale graphs and patterns, we propose a learning framework which augments different representation learning architectures and iteratively attends pattern and target data graphs to memorize subgraph isomorphisms for the global counting. We develop both small graphs (<= 1,024 subgraph isomorphisms in each) and large graphs (<= 4,096 subgraph isomorphisms in each) sets to evaluate different models. A mutagenic compound dataset, MUTAG, is also used to evaluate neural models and demonstrate the success of transfer learning. While the learning based approach is inexact, we are able to generalize to count large patterns and data graphs in linear time compared to the exponential time of the original NP-complete problem. Experimental results show that learning based subgraph isomorphism counting can speed up the traditional algorithm, VF2, 10-1,000 times with acceptable errors. Domain adaptation based on fine-tuning also shows the usefulness of our approach in real-world applications.

cs.LG↗

arXiv2019

Robust Sequence-to-Sequence Acoustic Modeling with Stepwise Monotonic Attention for Neural TTS

Neural TTS has demonstrated strong capabilities to generate human-like speech with high quality and naturalness, while its generalization to out-of-domain texts is still a challenging task, with regard to the design of attention-based sequence-to-sequence acoustic modeling. Various errors occur in those inputs with unseen context, including attention collapse, skipping, repeating, etc., which limits the broader applications. In this paper, we propose a novel stepwise monotonic attention method in sequence-to-sequence acoustic modeling to improve the robustness on out-of-domain inputs. The method utilizes the strict monotonic property in TTS with constraints on monotonic hard attention that the alignments between inputs and outputs sequence must be not only monotonic but allowing no skipping on inputs. Soft attention could be used to evade mismatch between training and inference. The experimental results show that the proposed method could achieve significant improvements in robustness on out-of-domain scenarios for phoneme-based models, without any regression on the in-domain naturalness test.

cs.CL↗