pwc-archive/papers-with-abstracts huggingface dataset:
Minimax Rate-Optimal Algorithms for High-Dimensional Stochastic Linear Bandits
Authors: Jingyu Liu, Yanglei Song
Date: 2025-05-23 00:00:00

We study the stochastic linear bandit problem with multiple arms over $T$ rounds, where the covariate dimension $d$ may exceed $T$, but each arm-specific parameter vector is $s$-sparse. We begin by analyzing the sequential estimation problem in the single-arm setting, focusing on cumulative mean-squared error. We show that Lasso estimators are provably suboptimal in the sequential setting, exhibiting suboptimal dependence on $d$ and $T$, whereas thresholded Lasso estimators -- obtained by applying least squares to the support selected by thresholding an initial Lasso estimator -- achieve the minimax rate. Building on these insights, we consider the full linear contextual bandit problem and propose a three-stage arm selection algorithm that uses thresholded Lasso as the main estimation method. We derive an upper bound on the cumulative regret of order $s(\log s)(\log d + \log T)$, and establish a matching lower bound up to a $\log s$ factor, thereby characterizing the minimax regret rate up to a logarithmic term in $s$. Moreover, when a short initial period is excluded from the regret, the proposed algorithm achieves exact minimax optimality.
Optimal Transport with Heterogeneously Missing Data
Authors: Linus Bleistein, Aurélien Bellet, Julie Josse
Date: 2025-05-22 00:00:00
Tasks: Matrix Completion, Missing Values

We consider the problem of solving the optimal transport problem between two empirical distributions with missing values. Our main assumption is that the data is missing completely at random (MCAR), but we allow for heterogeneous missingness probabilities across features and across the two distributions. As a first contribution, we show that the Wasserstein distance between empirical Gaussian distributions and linear Monge maps between arbitrary distributions can be debiased without significantly affecting the sample complexity. Secondly, we show that entropic regularized optimal transport can be estimated efficiently and consistently using iterative singular value thresholding (ISVT). We propose a validation set-free hyperparameter selection strategy for ISVT that leverages our estimator of the Bures-Wasserstein distance, which could be of independent interest in general matrix completion problems. Finally, we validate our findings on a wide range of numerical applications.
Representing local protein environments with atomistic foundation models
Authors: Meital Bojan, Sanketh Vedula, Advaith Maddipatla, Nadav Bojan Sellam, Federico Napoli, Paul Schanda, Alex M. Bronstein
Date: 2025-05-29 00:00:00

The local structure of a protein strongly impacts its function and interactions with other molecules. Therefore, a concise, informative representation of a local protein environment is essential for modeling and designing proteins and biomolecular interactions. However, these environments' extensive structural and chemical variability makes them challenging to model, and such representations remain under-explored. In this work, we propose a novel representation for a local protein environment derived from the intermediate features of atomistic foundation models (AFMs). We demonstrate that this embedding effectively captures both local structure (e.g., secondary motifs), and chemical features (e.g., amino-acid identity and protonation state). We further show that the AFM-derived representation space exhibits meaningful structure, enabling the construction of data-driven priors over the distribution of biomolecular environments. Finally, in the context of biomolecular NMR spectroscopy, we demonstrate that the proposed representations enable a first-of-its-kind physics-informed chemical shift predictor that achieves state-of-the-art accuracy. Our results demonstrate the surprising effectiveness of atomistic foundation models and their emergent representations for protein modeling beyond traditional molecular simulations. We believe this will open new lines of work in constructing effective functional representations for protein environments.
CFP-Gen: Combinatorial Functional Protein Generation via Diffusion Language Models
Authors: Junbo Yin, Chao Zha, Wenjia He, Chencheng Xu, Xin Gao
Date: 2025-05-28 00:00:00
Tasks: Language Modeling, Language Modelling, Protein Design

Existing PLMs generate protein sequences based on a single-condition constraint from a specific modality, struggling to simultaneously satisfy multiple constraints across different modalities. In this work, we introduce CFP-Gen, a novel diffusion language model for Combinatorial Functional Protein GENeration. CFP-Gen facilitates the de novo protein design by integrating multimodal conditions with functional, sequence, and structural constraints. Specifically, an Annotation-Guided Feature Modulation (AGFM) module is introduced to dynamically adjust the protein feature distribution based on composable functional annotations, e.g., GO terms, IPR domains and EC numbers. Meanwhile, the Residue-Controlled Functional Encoding (RCFE) module captures residue-wise interaction to ensure more precise control. Additionally, off-the-shelf 3D structure encoders can be seamlessly integrated to impose geometric constraints. We demonstrate that CFP-Gen enables high-throughput generation of novel proteins with functionality comparable to natural proteins, while achieving a high success rate in designing multifunctional proteins. Code and data available at https://github.com/yinjunbo/cfpgen.
HelixDesign-Binder: A Scalable Production-Grade Platform for Binder Design Built on HelixFold3
Authors: Jie Gao, Jun Li, Jing Hu, Shanzhuo Zhang, Kunrui Zhu, Yueyang Huang, Xiaonan Zhang, Xiaomin Fang
Date: 2025-05-28 00:00:00
Tasks: Benchmarking, Efficient Exploration

Protein binder design is central to therapeutics, diagnostics, and synthetic biology, yet practical deployment remains challenging due to fragmented workflows, high computational costs, and complex tool integration. We present HelixDesign-Binder, a production-grade, high-throughput platform built on HelixFold3 that automates the full binder design pipeline, from backbone generation and sequence design to structural evaluation and multi-dimensional scoring. By unifying these stages into a scalable and user-friendly system, HelixDesign-Binder enables efficient exploration of binder candidates with favorable structural, energetic, and physicochemical properties. The platform leverages Baidu Cloud's high-performance infrastructure to support large-scale design and incorporates advanced scoring metrics, including ipTM, predicted binding free energy, and interface hydrophobicity. Benchmarking across six protein targets demonstrates that HelixDesign-Binder reliably produces diverse and high-quality binders, some of which match or exceed validated designs in predicted binding affinity. HelixDesign-Binder is accessible via an interactive web interface in PaddleHelix platform, supporting both academic research and industrial applications in antibody and protein binder development.
Designing Cyclic Peptides via Harmonic SDE with Atom-Bond Modeling
Authors: Xiangxin Zhou, Mingyu Li, Yi Xiao, Jiahan Li, Dongyu Xue, Zaixiang Zheng, Jianzhu Ma, Quanquan Gu
Date: 2025-05-27 00:00:00

Cyclic peptides offer inherent advantages in pharmaceuticals. For example, cyclic peptides are more resistant to enzymatic hydrolysis compared to linear peptides and usually exhibit excellent stability and affinity. Although deep generative models have achieved great success in linear peptide design, several challenges prevent the development of computational methods for designing diverse types of cyclic peptides. These challenges include the scarcity of 3D structural data on target proteins and associated cyclic peptide ligands, the geometric constraints that cyclization imposes, and the involvement of non-canonical amino acids in cyclization. To address the above challenges, we introduce CpSDE, which consists of two key components: AtomSDE, a generative structure prediction model based on harmonic SDE, and ResRouter, a residue type predictor. Utilizing a routed sampling algorithm that alternates between these two models to iteratively update sequences and structures, CpSDE facilitates the generation of cyclic peptides. By employing explicit all-atom and bond modeling, CpSDE overcomes existing data limitations and is proficient in designing a wide variety of cyclic peptides. Our experimental results demonstrate that the cyclic peptides designed by our method exhibit reliable stability and affinity.
TumorHoPe2: An updated database for Tumor Homing Peptides
Authors: Diksha Kashyap, Devanshi Gupta, Naman Kumar Mehta, Gajendra P. S. Raghava
Date: 2025-05-27 00:00:00
Tasks: Specificity

Addressing the growing need for organized data on tumor homing peptides (THPs), we present TumorHoPe2, a manually curated database offering extensive details on experimentally validated THPs. This represents a significant update to TumorHoPe, originally developed by our group in 2012. TumorHoPe2 now contains 1847 entries, representing 1297 unique tumor homing peptides, a substantial expansion from the 744 entries in its predecessor. For each peptide, the database provides critical information, including sequence, terminal or chemical modifications, corresponding cancer cell lines, and specific tumor types targeted. The database compiles data from two primary sources: phage display libraries, which are commonly used to identify peptide ligands targeting tumor-specific markers, and synthetic peptides, which are chemically modified to enhance properties such as stability, binding affinity, and specificity. Our dataset includes 594 chemically modified peptides, with 255 having N-terminal and 195 C-terminal modifications. These THPs have been validated against 172 cancer cell lines and demonstrate specificity for 37 distinct tumor types. To maximize utility for the research community, TumorHoPe2 is equipped with intuitive tools for data searching, filtering, and analysis, alongside a RESTful API for efficient programmatic access and integration into bioinformatics pipelines. It is freely available at https://webs.iiitd.edu.in/raghava/tumorhope2/
PDFBench: A Benchmark for De novo Protein Design from Function
Authors: Jiahao Kuang, Nuowei Liu, Changzhi Sun, Tao Ji, Yuanbin Wu
Date: 2025-05-25 00:00:00
Tasks: Protein Design

In recent years, while natural language processing and multimodal learning have seen rapid advancements, the field of de novo protein design has also experienced significant growth. However, most current methods rely on proprietary datasets and evaluation rubrics, making fair comparisons between different approaches challenging. Moreover, these methods often employ evaluation metrics that capture only a subset of the desired properties of designed proteins, lacking a comprehensive assessment framework. To address these, we introduce PDFBench, the first comprehensive benchmark for evaluating de novo protein design from function. PDFBench supports two tasks: description-guided design and keyword-guided design. To ensure fair and multifaceted evaluation, we compile 22 metrics covering sequence plausibility, structural fidelity, and language-protein alignment, along with measures of novelty and diversity. We evaluate five state-of-the-art baselines, revealing their respective strengths and weaknesses across tasks. Finally, we analyze inter-metric correlations, exploring the relationships between four categories of metrics, and offering guidelines for metric selection. PDFBench establishes a unified framework to drive future advances in function-driven de novo protein design.
Atomic Density Distributions in Proteins: Structural and Functional Implications
Authors: Sotirios Touliopoulos, Nicholas M. Glykos
Date: 2025-05-24 00:00:00

Atomic packing is an important metric for characterizing protein structures, as it significantly influences various features including the stability, the rate of evolution and the functional roles of proteins. Packing in protein structures is a measure of the overall proximity between the proteins' atoms and it can vary notably among different structures. However, even single domain proteins do not exhibit uniform packing throughout their structure. Many different methods have been used to measure the quality of packing in proteins, identify factors that influence it, and their possible implications. In this work, we examine atomic density distributions derived from 21,255 non-redundant protein structures and show that statistically significant differences between those distributions are present. The biomolecular assembly unit was chosen as a representative for these structures. Several protein structures deviate significantly and systematically from the average packing behavior. Hierarchical clustering indicated that there are groups of structures with similar atomic density distributions. Search for common features and patterns in these clusters showed that some of them include proteins with characteristic structures such as coiled-coils and cytochromes. Certain classification families such as hydrolases and transferases have also a preference to appear more frequently in dense and loosely-packed clusters respectively. Regarding factors influencing packing, our results support knowledge that larger structures have a smaller range in their density values, but tend to be more loosely packed, compared to smaller proteins. We also used indicators, like crystallographic water molecules abundance and B-factors as estimates of the stability of the structures to reveal its relationship with packing.
Flexible MOF Generation with Torsion-Aware Flow Matching
Authors: Nayoung Kim, Seongsu Kim, Sungsoo Ahn
Date: 2025-05-23 00:00:00
Tasks: valid

Designing metal-organic frameworks (MOFs) with novel chemistries is a long-standing challenge due to their large combinatorial space and the complex 3D arrangements of building blocks. While recent deep generative models have enabled scalable MOF generation, they assume (1) a fixed set of building blocks and (2) known ground-truth local block-wise 3D coordinates. However, this limits their ability to (1) design novel MOFs and (2) generate the structure using novel building blocks. We propose a two-stage de novo MOF generation framework that overcomes these limitations by modeling both chemical and geometric degrees of freedom. First, we train a SMILES-based autoregressive model to generate novel metal and organic building blocks, paired with cheminformatics for 3D structure initialization. Second, we introduce a flow-matching model that predicts translations, rotations, and torsional angles to assemble flexible blocks into valid 3D frameworks. Our experiments demonstrate improved reconstruction accuracy, the generation of valid, novel, and unique MOFs, and the ability of our model to create novel building blocks.
Predicting protein folding dynamics using sequence information
Authors: Ezequiel A. Galpern, Federico Caamaño, Diego U. Ferreiro
Date: 2025-05-22 00:00:00
Tasks: Protein Folding

Natural protein sequences somehow encode the structural forms that these molecules adopt. Recent developments in structure-prediction are agnostic to the mechanisms by which proteins fold and represent them as static objects. However, the amino acid sequences also encode information about how the folding process can happen, and how variations in the sequences impact on the populations of the distinct structural forms that proteins acquire. Here we present a method to infer protein folding dynamics based only on sequence information. For this, we will rely first on the obtention of a precise 'evolutionary field' from the observed variations in the sequences of homologous proteins. We then show how to map the energetics to a coarse-grained folding model where the protein is treated as a string of foldons that interact. We then describe how, for any given protein sequence of a family, the equilibrium folding curve can be computed and how the emergence of protein folding sub-domains can be identified. We finally present protocols to analyze how mutations perturb both the folding stability and the cooperativity, that represent predictions for a deep-mutational scan of a protein of interest.
PSBench: a large-scale benchmark for estimating the accuracy of protein complex structural models
Authors: Pawan Neupane, Jian Liu, Jianlin Cheng
Date: 2025-05-13 00:00:00
Tasks: Drug Discovery, Protein Design, Protein Structure Prediction

Predicting protein complex structures is essential for protein function analysis, protein design, and drug discovery. While AI methods like AlphaFold can predict accurate structural models for many protein complexes, reliably estimating the quality of these predicted models (estimation of model accuracy, or EMA) for model ranking and selection remains a major challenge. A key barrier to developing effective machine learning-based EMA methods is the lack of large, diverse, and well-annotated datasets for training and evaluation. To address this gap, we introduce PSBench, a benchmark suite comprising four large-scale, labeled datasets generated during the 15th and 16th community-wide Critical Assessment of Protein Structure Prediction (CASP15 and CASP16). PSBench includes over one million structural models covering a wide range of protein sequence lengths, complex stoichiometries, functional classes, and modeling difficulties. Each model is annotated with multiple complementary quality scores at the global, local, and interface levels. PSBench also provides multiple evaluation metrics and baseline EMA methods to facilitate rigorous comparisons. To demonstrate PSBench's utility, we trained and evaluated GATE, a graph transformer-based EMA method, on the CASP15 data. GATE was blindly tested in CASP16 (2024), where it ranked among the top-performing EMA methods. These results highlight PSBench as a valuable resource for advancing EMA research in protein complex modeling. PSBench is publicly available at: https://github.com/BioinfoMachineLearning/PSBench.
Sensitivity analysis-guided model reduction of a mathematical model of pembrolizumab therapy for de novo metastatic MSI-H/dMMR colorectal cancer
Authors: Georgio Hawi, Peter S. Kim, Peter P. Lee
Date: 2025-05-25 00:00:00

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and the leading cause of cancer-related deaths in adults under 55, involving a complex interplay of biological processes such as dendritic cell (DC) maturation and migration, T cell activation and proliferation, cytokine production, and T cell and natural killer (NK) cell-mediated cancer cell killing. Microsatellite instability-high (MSI-H) CRC and deficient mismatch repair (dMMR) CRC constitute 15% of all CRC, and 4% of metastatic CRC, and exhibit remarkable responsiveness to immunotherapy, especially with PD-1 inhibitors such as pembrolizumab. Mathematical models of the underlying immunobiology and the interactions underpinning immune checkpoint blockade offer mechanistic insights into tumour-immune dynamics and provide avenues for treatment optimisation and the identification of novel therapeutic targets. We used our data-driven model of de novo metastatic MSI-H/dMMR CRC (dnmMCRC) and performed sensitivity analysis-guided model reduction using the FAST and EFAST methods. In this work, we constructed two simplified models of dnmMCRC: one that faithfully reproduces all of the original model's trajectories, and a second, minimal model that accurately replicates the original dynamics while being highly extensible for future inclusion of additional components to explore various aspects of the anti-tumour immune response.
Quantitative analysis of cell size control mechanisms
Authors: Shuqi Fan, Jinzhi Lei
Date: 2025-05-26 00:00:00

Cell size control is crucial for maintaining cellular function and homeostasis. In this study, we develop a first-order partial differential equation model to examine the effects of three key size control mechanisms: the sizer, timer, and adder. Each mechanism is incorporated into the model through distinct boundary conditions. Exact solutions for these mechanisms are derived using the method of characteristics, allowing us to explore how the steady-state size distribution depends on control parameters. Additionally, individual-cell-based stochastic simulations are performed to validate our theoretical findings and investigate the size distribution under various conditions. This study provides new insights into the quantitative dynamics of cell size regulation, highlighting the underlying mechanisms and laying the groundwork for future theoretical and experimental work on size homeostasis in biological systems.
HAD: Hybrid Architecture Distillation Outperforms Teacher in Genomic Sequence Modeling
Authors: Hexiong Yang, Mingrui Chen, Huaibo Huang, Junxian Duan, Jie Cao, Zhen Zhou, Ran He
Date: 2025-05-27 00:00:00
Tasks: Language Modeling, Language Modelling, Masked Language Modeling

Inspired by the great success of Masked Language Modeling (MLM) in the natural language domain, the paradigm of self-supervised pre-training and fine-tuning has also achieved remarkable progress in the field of DNA sequence modeling. However, previous methods often relied on massive pre-training data or large-scale base models with huge parameters, imposing a significant computational burden. To address this, many works attempted to use more compact models to achieve similar outcomes but still fell short by a considerable margin. In this work, we propose a Hybrid Architecture Distillation (HAD) approach, leveraging both distillation and reconstruction tasks for more efficient and effective pre-training. Specifically, we employ the NTv2-500M as the teacher model and devise a grouping masking strategy to align the feature embeddings of visible tokens while concurrently reconstructing the invisible tokens during MLM pre-training. To validate the effectiveness of our proposed method, we conducted comprehensive experiments on the Nucleotide Transformer Benchmark and Genomic Benchmark. Compared to models with similar parameters, our model achieved excellent performance. More surprisingly, it even surpassed the distillation ceiling-teacher model on some sub-tasks, which is more than 500 $\times$ larger. Lastly, we utilize t-SNE for more intuitive visualization, which shows that our model can gain a sophisticated understanding of the intrinsic representation pattern in genomic sequences.
Ctrl-DNA: Controllable Cell-Type-Specific Regulatory DNA Design via Constrained RL
Authors: Xingyu Chen, Shihao Ma, Runsheng Lin, Jiecong Lin, Bo wang
Date: 2025-05-26 00:00:00
Tasks: Reinforcement Learning (RL), Specificity

Designing regulatory DNA sequences that achieve precise cell-type-specific gene expression is crucial for advancements in synthetic biology, gene therapy and precision medicine. Although transformer-based language models (LMs) can effectively capture patterns in regulatory DNA, their generative approaches often struggle to produce novel sequences with reliable cell-specific activity. Here, we introduce Ctrl-DNA, a novel constrained reinforcement learning (RL) framework tailored for designing regulatory DNA sequences with controllable cell-type specificity. By formulating regulatory sequence design as a biologically informed constrained optimization problem, we apply RL to autoregressive genomic LMs, enabling the models to iteratively refine sequences that maximize regulatory activity in targeted cell types while constraining off-target effects. Our evaluation on human promoters and enhancers demonstrates that Ctrl-DNA consistently outperforms existing generative and RL-based approaches, generating high-fitness regulatory sequences and achieving state-of-the-art cell-type specificity. Moreover, Ctrl-DNA-generated sequences capture key cell-type-specific transcription factor binding sites (TFBS), short DNA motifs recognized by regulatory proteins that control gene expression, demonstrating the biological plausibility of the generated sequences.