pwc-archive/papers-with-abstracts huggingface dataset:
Leveraging Optimal Transport for Distributed Two-Sample Testing: An Integrated Transportation Distance-based Framework
Authors: Zhengqi Lin, Yan Chen
Date: 2025-06-19 00:00:00
Tasks: Federated Learning, Two-sample testing

This paper introduces a novel framework for distributed two-sample testing using the Integrated Transportation Distance (ITD), an extension of the Optimal Transport distance. The approach addresses the challenges of detecting distributional changes in decentralized learning or federated learning environments, where data privacy and heterogeneity are significant concerns. We provide theoretical foundations for the ITD, including convergence properties and asymptotic behavior. A permutation test procedure is proposed for practical implementation in distributed settings, allowing for efficient computation while preserving data privacy. The framework's performance is demonstrated through theoretical power analysis and extensive simulations, showing robust Type I error control and high power across various distributions and dimensions. The results indicate that ITD effectively aggregates information across distributed clients, detecting subtle distributional shifts that might be missed when examining individual clients. This work contributes to the growing field of distributed statistical inference, offering a powerful tool for two-sample testing in modern, decentralized data environments.
Identifiability by common backdoor in summary causal graphs of time series
Authors: Clément Yvernes, Charles K. Assaad, Emilie Devijver, Eric Gaussier
Date: 2025-06-17 00:00:00
Tasks: Time Series

The identifiability problem for interventions aims at assessing whether the total effect of some given interventions can be written with a do-free formula, and thus be computed from observational data only. We study this problem, considering multiple interventions and multiple effects, in the context of time series when only abstractions of the true causal graph in the form of summary causal graphs are available. We focus in this study on identifiability by a common backdoor set, and establish, for time series with and without consistency throughout time, conditions under which such a set exists. We also provide algorithms of limited complexity to decide whether the problem is identifiable or not.
Beyond Sin-Squared Error: Linear-Time Entrywise Uncertainty Quantification for Streaming PCA
Authors: Syamantak Kumar, Shourya Pandey, Purnamrita Sarkar
Date: 2025-06-14 00:00:00
Tasks: Uncertainty Quantification

We propose a novel statistical inference framework for streaming principal component analysis (PCA) using Oja's algorithm, enabling the construction of confidence intervals for individual entries of the estimated eigenvector. Most existing works on streaming PCA focus on providing sharp sin-squared error guarantees. Recently, there has been some interest in uncertainty quantification for the sin-squared error. However, uncertainty quantification or sharp error guarantees for entries of the estimated eigenvector in the streaming setting remains largely unexplored. We derive a sharp Bernstein-type concentration bound for elements of the estimated vector matching the optimal error rate up to logarithmic factors. We also establish a Central Limit Theorem for a suitably centered and scaled subset of the entries. To efficiently estimate the coordinate-wise variance, we introduce a provably consistent subsampling algorithm that leverages the median-of-means approach, empirically achieving similar accuracy to multiplier bootstrap methods while being significantly more computationally efficient. Numerical experiments demonstrate its effectiveness in providing reliable uncertainty estimates with a fraction of the computational cost of existing methods.
Bridging Classical Molecular Dynamics and Quantum Foundations for Comprehensive Protein Structural Analysis
Authors: Don Roosan, Rubayat Khan, Tiffany Khou, Saif Nirzhor, Fahmida Hai, Brian Provencher
Date: 2025-06-25 00:00:00

The objective of this paper is to investigate the structural stability, dynamic properties, and potential interactions among Amyloid Precursor Protein (APP), Tau, and Alpha-synuclein through a series of molecular dynamics simulations that integrate publicly available structural data, detailed force-field parameters, and comprehensive analytical protocols. By focusing on these three proteins, which are each implicated in various neurodegenerative disorders, the study aims to elucidate how their conformational changes and interprotein contact sites may influence larger biological processes. Through rigorous evaluation of their folding behaviors, energetic interactions, and residue-specific functions, this work contributes to the broader understanding of protein aggregation mechanisms and offers insights that may ultimately guide therapeutic intervention strategies.
ProCaliper: functional and structural analysis, visualization, and annotation of proteins
Authors: Jordan C. Rozum, Hunter Ufford, Alexandria K. Im, Tong Zhang, David D. Pollock, Doo Nam Kim, Song Feng
Date: 2025-06-24 00:00:00

Understanding protein function at the molecular level requires connecting residue-level annotations with physical and structural properties. This can be cumbersome and error-prone when functional annotation, computation of physico-chemical properties, and structure visualization are separated. To address this, we introduce ProCaliper, an open-source Python library for computing and visualizing physico-chemical properties of proteins. It can retrieve annotation and structure data from UniProt and AlphaFold databases, compute residue-level properties such as charge, solvent accessibility, and protonation state, and interactively visualize the results of these computations along with user-supplied residue-level data. Additionally, ProCaliper incorporates functional and structural information to construct and optionally sparsify networks that encode the distance between residues and/or annotated functional sites or regions. The package ProCaliper and its source code, along with the code used to generate the figures in this manuscript, are freely available at https://github.com/PNNL-Predictive-Phenomics/ProCaliper.
A standard transformer and attention with linear biases for molecular conformer generation
Authors: Viatcheslav Gurev, Timothy Rumbell
Date: 2025-06-24 00:00:00
Tasks: Drug Discovery

Sampling low-energy molecular conformations, spatial arrangements of atoms in a molecule, is a critical task for many different calculations performed in the drug discovery and optimization process. Numerous specialized equivariant networks have been designed to generate molecular conformations from 2D molecular graphs. Recently, non-equivariant transformer models have emerged as a viable alternative due to their capability to scale to improve generalization. However, the concern has been that non-equivariant models require a large model size to compensate the lack of equivariant bias. In this paper, we demonstrate that a well-chosen positional encoding effectively addresses these size limitations. A standard transformer model incorporating relative positional encoding for molecular graphs when scaled to 25 million parameters surpasses the current state-of-the-art non-equivariant base model with 64 million parameters on the GEOM-DRUGS benchmark. We implemented relative positional encoding as a negative attention bias that linearly increases with the shortest path distances between graph nodes at varying slopes for different attention heads, similar to ALiBi, a widely adopted relative positional encoding technique in the NLP domain. This architecture has the potential to serve as a foundation for a novel class of generative models for molecular conformations.
ProxelGen: Generating Proteins as 3D Densities
Authors: Felix Faltings, Hannes Stark, Regina Barzilay, Tommi Jaakkola
Date: 2025-06-24 00:00:00

We develop ProxelGen, a protein structure generative model that operates on 3D densities as opposed to the prevailing 3D point cloud representations. Representing proteins as voxelized densities, or proxels, enables new tasks and conditioning capabilities. We generate proteins encoded as proxels via a 3D CNN-based VAE in conjunction with a diffusion model operating on its latent space. Compared to state-of-the-art models, ProxelGen's samples achieve higher novelty, better FID scores, and the same level of designability as the training set. ProxelGen's advantages are demonstrated in a standard motif scaffolding benchmark, and we show how 3D density-based generation allows for more flexible shape conditioning.
Toward the Explainability of Protein Language Models for Sequence Design
Authors: Andrea Hunklinger, Noelia Ferruz
Date: 2025-06-24 00:00:00
Tasks: Explainable artificial intelligence, Explainable Artificial Intelligence (XAI), Protein Design

Transformer-based language models excel in a variety of protein-science tasks that range from structure prediction to the design of functional enzymes. However, these models operate as black boxes, and their underlying working principles remain unclear. Here, we survey emerging applications of explainable artificial intelligence (XAI) to protein language models (pLMs) and describe their potential in protein research. We break down the workflow of a generative decoder-only Transformer into four information contexts: (i) training sequences, (ii) input prompt, (iii) model architecture, and (iv) output sequence. For each, we describe existing methods and applications of XAI. Additionally, from published studies we distil five (potential) roles that XAI can play in protein design: Evaluator, Multitasker, Engineer, Coach, and Teacher, with the Evaluator role being the only one widely adopted so far. These roles aim to help both protein science practitioners and model developers understand the possibilities and limitations of implementing XAI for the design of sequences. Finally, we highlight the critical areas of application for the future, including risks related to security, trustworthiness, and bias, and we call for community benchmarks, open-source tooling, and domain-specific visualizations to advance explainable protein design. Overall, our analysis aims to move the discussion toward the use of XAI in protein design.
Generative Modeling of Full-Atom Protein Conformations using Latent Diffusion on Graph Embeddings
Authors: Aditya Sengar, Ali Hariri, Daniel Probst, Patrick Barth, Pierre Vandergheynst
Date: 2025-06-20 00:00:00
Tasks: Graph Neural Network

Generating diverse, all-atom conformational ensembles of dynamic proteins such as G-protein-coupled receptors (GPCRs) is critical for understanding their function, yet most generative models simplify atomic detail or ignore conformational diversity altogether. We present latent diffusion for full protein generation (LD-FPG), a framework that constructs complete all-atom protein structures, including every side-chain heavy atom, directly from molecular dynamics (MD) trajectories. LD-FPG employs a Chebyshev graph neural network (ChebNet) to obtain low-dimensional latent embeddings of protein conformations, which are processed using three pooling strategies: blind, sequential and residue-based. A diffusion model trained on these latent representations generates new samples that a decoder, optionally regularized by dihedral-angle losses, maps back to Cartesian coordinates. Using D2R-MD, a 2-microsecond MD trajectory (12 000 frames) of the human dopamine D2 receptor in a membrane environment, the sequential and residue-based pooling strategy reproduces the reference ensemble with high structural fidelity (all-atom lDDT of approximately 0.7; C-alpha-lDDT of approximately 0.8) and recovers backbone and side-chain dihedral-angle distributions with a Jensen-Shannon divergence of less than 0.03 compared to the MD data. LD-FPG thereby offers a practical route to system-specific, all-atom ensemble generation for large proteins, providing a promising tool for structure-based therapeutic design on complex, dynamic targets. The D2R-MD dataset and our implementation are freely available to facilitate further research.
Single-Cell Proteomic Technologies: Tools in the quest for principles
Authors: Nikolai Slavov
Date: 2025-06-22 00:00:00

Over the last decade, proteomic analysis of single cells by mass spectrometry transitioned from an uncertain possibility to a set of robust and rapidly advancing technologies supporting the accurate quantification of thousands of proteins. We review the major drivers of this progress, from establishing feasibility to powerful and increasingly scalable methods. We focus on the tradeoffs and synergies of different technological solutions within a coherent conceptual framework, which projects considerable room both for throughput scaling and for extending the analysis scope to functional protein measurements. We highlight the potential of these technologies to support the development of mechanistic biophysical models and help uncover new principles.
OmniESI: A unified framework for enzyme-substrate interaction prediction with progressive conditional deep learning
Authors: Zhiwei Nie, Hongyu Zhang, Hao Jiang, Yutian Liu, Xiansong Huang, Fan Xu, Jie Fu, Zhixiang Ren, Yonghong Tian, Wen-Bin Zhang, Jie Chen
Date: 2025-06-22 00:00:00
Tasks: Parameter Prediction, Prediction, Specificity

Understanding and modeling enzyme-substrate interactions is crucial for catalytic mechanism research, enzyme engineering, and metabolic engineering. Although a large number of predictive methods have emerged, they do not incorporate prior knowledge of enzyme catalysis to rationally modulate general protein-molecule features that are misaligned with catalytic patterns. To address this issue, we introduce a two-stage progressive framework, OmniESI, for enzyme-substrate interaction prediction through conditional deep learning. By decomposing the modeling of enzyme-substrate interactions into a two-stage progressive process, OmniESI incorporates two conditional networks that respectively emphasize enzymatic reaction specificity and crucial catalysis-related interactions, facilitating a gradual feature modulation in the latent space from general protein-molecule domain to catalysis-aware domain. On top of this unified architecture, OmniESI can adapt to a variety of downstream tasks, including enzyme kinetic parameter prediction, enzyme-substrate pairing prediction, enzyme mutational effect prediction, and enzymatic active site annotation. Under the multi-perspective performance evaluation of in-distribution and out-of-distribution settings, OmniESI consistently delivered superior performance than state-of-the-art specialized methods across seven benchmarks. More importantly, the proposed conditional networks were shown to internalize the fundamental patterns of catalytic efficiency while significantly improving prediction performance, with only negligible parameter increases (0.16%), as demonstrated by ablation studies on key components. Overall, OmniESI represents a unified predictive approach for enzyme-substrate interactions, providing an effective tool for catalytic mechanism cracking and enzyme engineering with strong generalization and broad applicability.
AbRank: A Benchmark Dataset and Metric-Learning Framework for Antibody-Antigen Affinity Ranking
Authors: Chunan Liu, Aurelien Pelissier, Yanjun Shao, Lilian Denzler, Andrew C. R. Martin, Brooks Paige, Mariia Rodriguez Martinez
Date: 2025-06-21 00:00:00
Tasks: Metric Learning, Protein Language Model

Accurate prediction of antibody-antigen (Ab-Ag) binding affinity is essential for therapeutic design and vaccine development, yet the performance of current models is limited by noisy experimental labels, heterogeneous assay conditions, and poor generalization across the vast antibody and antigen sequence space. We introduce AbRank, a large-scale benchmark and evaluation framework that reframes affinity prediction as a pairwise ranking problem. AbRank aggregates over 380,000 binding assays from nine heterogeneous sources, spanning diverse antibodies, antigens, and experimental conditions, and introduces standardized data splits that systematically increase distribution shift, from local perturbations such as point mutations to broad generalization across novel antigens and antibodies. To ensure robust supervision, AbRank defines an m-confident ranking framework by filtering out comparisons with marginal affinity differences, focusing training on pairs with at least an m-fold difference in measured binding strength. As a baseline for the benchmark, we introduce WALLE-Affinity, a graph-based approach that integrates protein language model embeddings with structural information to predict pairwise binding preferences. Our benchmarks reveal significant limitations in current methods under realistic generalization settings and demonstrate that ranking-based training improves robustness and transferability. In summary, AbRank offers a robust foundation for machine learning models to generalize across the antibody-antigen space, with direct relevance for scalable, structure-aware antibody therapeutic design.
Aptamer-protein interaction prediction model based on transformer
Authors: Zhichao Yan, Yue Kang, Buyong Ma
Date: 2025-06-19 00:00:00
Tasks: Prediction

Aptamers are single-stranded DNA/RNAs or short peptides with unique tertiary structures that selectively bind to specific targets. They have great potential in the detection and medical fields. Here, we present SelfTrans-Ensemble, a deep learning model that integrates sequence information models and structural information models to extract multi-scale features for predicting aptamer-protein interactions (APIs). The model employs two pre-trained models, ProtBert and RNA-FM, to encode protein and aptamer sequences, along with features generated from primary sequence and secondary structural information. To address the data imbalance in the aptamer dataset imbalance, we incorporated short RNA-protein interaction data in the training set. This resulted in a training accuracy of 98.9% and a test accuracy of 88.0%, demonstrating the model's effectiveness in accurately predicting APIs. Additionally, analysis using molecular simulation indicated that SelfTrans-Ensemble is sensitive to aptamer sequence mutations. We anticipate that SelfTrans-Ensemble can offer a more efficient and rapid process for aptamer screening.
Active Learning-Guided Seq2Seq Variational Autoencoder for Multi-target Inhibitor Generation
Authors: Júlia Vilalta-Mor, Alexis Molina, Laura Ortega Varga, Isaac Filella-Merce, Victor Guallar
Date: 2025-06-18 00:00:00
Tasks: Active Learning, Diversity, Drug Design, Drug Discovery

Simultaneously optimizing molecules against multiple therapeutic targets remains a profound challenge in drug discovery, particularly due to sparse rewards and conflicting design constraints. We propose a structured active learning (AL) paradigm integrating a sequence-to-sequence (Seq2Seq) variational autoencoder (VAE) into iterative loops designed to balance chemical diversity, molecular quality, and multi-target affinity. Our method alternates between expanding chemically feasible regions of latent space and progressively constraining molecules based on increasingly stringent multi-target docking thresholds. In a proof-of-concept study targeting three related coronavirus main proteases (SARS-CoV-2, SARS-CoV, MERS-CoV), our approach efficiently generated a structurally diverse set of pan-inhibitor candidates. We demonstrate that careful timing and strategic placement of chemical filters within this active learning pipeline markedly enhance exploration of beneficial chemical space, transforming the sparse-reward, multi-objective drug design problem into an accessible computational task. Our framework thus provides a generalizable roadmap for efficiently navigating complex polypharmacological landscapes.
CBTOPE2: An improved method for predicting of conformational B-cell epitopes in an antigen from its primary sequence
Authors: Anupma Pandey, Megha, Nishant Kumar, Ruchir Sahni, Gajendra P. S. Raghava
Date: 2025-06-16 00:00:00
Tasks: Hyperparameter Optimization

In 2009, our group pioneered a novel method CBTOPE for predicting conformational B-cell epitopes in a protein from its amino acid sequence, which received extensive citations from the scientific community. In a recent study, Cia et al. (2023) evaluated the performance of conformational B-cell epitope prediction methods on a well-curated dataset, revealing that most approaches, including CBTOPE, exhibited poor performance. One plausible cause of this diminished performance is that available methods were trained on datasets that are both limited in size and outdated in content. In this study, we present an enhanced version of CBTOPE, trained, tested, and evaluated using the well-curated dataset from Cai et al. (2023). Initially, we developed machine learning-based models using binary profiles, achieving a maximum AUC of 0.58 on the validation dataset. The performance of our method improved significantly from an AUC of 0.58 to 0.63 when incorporating evolutionary information in the form of a Position-Specific Scoring Matrix (PSSM) profile. Furthermore, the performance increased from an AUC of 0.63 to 0.64 when we integrated both the PSSM profile and relative solvent accessibility (RSA). All models were trained, tested, and optimized on the training dataset using five-fold cross-validation. The final performance of our models was assessed using a validation or independent dataset that was not used during hyperparameter optimization. To facilitate scientific community working in the field of subunit vaccine, we develop a standalone software and web server CBTOPE2 (https://webs.iiitd.edu.in/raghava/cbtope2/).
LapDDPM: A Conditional Graph Diffusion Model for scRNA-seq Generation with Spectral Adversarial Perturbations
Authors: Lorenzo Bini, Stephane Marchand-Maillet
Date: 2025-06-16 00:00:00

Generating high-fidelity and biologically plausible synthetic single-cell RNA sequencing (scRNA-seq) data, especially with conditional control, is challenging due to its high dimensionality, sparsity, and complex biological variations. Existing generative models often struggle to capture these unique characteristics and ensure robustness to structural noise in cellular networks. We introduce LapDDPM, a novel conditional Graph Diffusion Probabilistic Model for robust and high-fidelity scRNA-seq generation. LapDDPM uniquely integrates graph-based representations with a score-based diffusion model, enhanced by a novel spectral adversarial perturbation mechanism on graph edge weights. Our contributions are threefold: we leverage Laplacian Positional Encodings (LPEs) to enrich the latent space with crucial cellular relationship information; we develop a conditional score-based diffusion model for effective learning and generation from complex scRNA-seq distributions; and we employ a unique spectral adversarial training scheme on graph edge weights, boosting robustness against structural variations. Extensive experiments on diverse scRNA-seq datasets demonstrate LapDDPM's superior performance, achieving high fidelity and generating biologically-plausible, cell-type-specific samples. LapDDPM sets a new benchmark for conditional scRNA-seq data generation, offering a robust tool for various downstream biological applications.