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01.
arXiv (CS.LG) 2026-06-25

Adaptive Cumulative Mass Calibration with Conformal Prediction

arXiv:2505.15437v3 Announce Type: replace-cross Abstract: Reliable probability estimates by classifiers are essential in high-risk applications. In practice, however, predicted probabilities are often miscalibrated, and many existing post-hoc calibration methods typically lack guarantees that a specific notion of calibration is achieved after the correction procedure is applied. We introduce a set-based perspective on calibration through the notion of cumulative mass calibration and the corresponding error measures. We propose a new calibration procedure based on conformal prediction that forms cumulative probabilities with guaranteed marginal coverage. We introduce an adaptive temperature scaling algorithm, with the temperature tuned for each input to satisfy the conformal coverage constraint. As we show, this procedure can be efficiently implemented. Across image classification tasks, particularly in settings with many classes, our method improves newly introduced calibration error measures (CMCE and $\alpha$-CMCE) and standard metrics (such as ECE, cw-ECE, MCE) over the existing baselines.

02.
arXiv (CS.CV) 2026-06-25

AISPO: Enhancing Depth Reliability for Robotic Manipulation of Non-Lambertian Objects via Affine-Invariant Shape Prior

Reliable depth perception is critical for robotic manipulation, especially for non-Lambertian objects such as transparent or highly specular surfaces, where raw depth measurements are often corrupted or missing. These failures frequently propagate to motion planning, resulting in invalid grasp poses and execution errors. We propose AISPO, a depth completion framework that improves depth reliability for manipulation in challenging sensing conditions. AISPO combines multi-scale RGB-D feature fusion with an affine-invariant shape prior to enforce geometric consistency and mitigate catastrophic depth failures. Unlike methods that focus primarily on average depth accuracy, our approach emphasizes physical plausibility and structural integrity of the predicted depth maps. Extensive benchmark evaluations demonstrate competitive performance and strong generalization to unseen objects and novel scenes. Real-world grasping experiments further show that enhanced depth reliability significantly improves manipulation success rates, particularly for transparent objects where many existing methods fail to produce physically usable depth estimates.

03.
arXiv (CS.CV) 2026-06-18

Clinically Aligned Geometry Constraints for Robust IVUS Vessel Boundary Segmentation

Intravascular ultrasound (IVUS) lumen and external elastic membrane (EEM) segmentation is important for quantitative coronary plaque burden assessment. Errors in lumen or EEM delineation directly propagate to plaque area, plaque burden and geometric measurements. However, standard methods prioritising overlap scores often suffer from boundary drift and topology errors, leading to inaccurate clinical measurements. We present GeoCat, a geometry-consistent network that processes 5-frame IVUS clips using dual Cartesian-polar encoders with cross-domain attention and temporal fusion. A differentiable geometry consistency loss directly supervises clinically relevant descriptors including diameters, orientations, and cross-sectional areas. The model is trained on 12,242 annotated frames from 146 patients acquired with two commercial IVUS systems. We evaluate performance using both segmentation accuracy and plaque-relevant clinical metrics, including Dice/IoU, boundary measures(95HD (mm), ASSD), topology violation rate, and clinical geometry errors (dmax/dmin, angles, and areas). On our dataset, GeoCat achieves a Dice of 0.93, reduces 95HD to 0.14 mm, and lowers topology violations to 1.0%. Importantly, it significantly improves geometric fidelity, yielding diameter errors of 0.13-0.16 mm and angular errors of ~8 degrees, supporting reliable plaque burden quantification.

04.
PLOS Computational Biology 2026-06-04

CIPHER: An end-to-end framework for designing optimized aggregated spatial transcriptomics experiments

by Zachary Hemminger, Haley De Ocampo, Fangming Xie, Zhiqian Zhai, Jingyi Jessica Li, Roy Wollman Motivation Most imaging-based spatial transcriptomics methods measure individual genes, which limits scalability and typically requires integration with scRNA-seq to recover full cellular states. Recent approaches such as CISI, FISHnCHIPs, and ATLAS address this limitation by measuring aggregate transcriptional signatures, where multiple genes are pooled into each channel to increase throughput. While aggregate measurements improve scalability, they shift the problem from gene selection to feature design. For effective integration with scRNA-seq, these signatures must be not only discriminative in transcriptional space but also straightforward to measure, with balanced signal, sufficient dynamic range, and robustness to experimental noise. By optimizing decoding accuracy in isolation, existing methods leave substantial performance on the table. Results We present CIPHER (Cell Identity Projection using Hybridization Encoding Rules), a neural-network framework that jointly optimizes the experimental encoding matrix, i.e., the way that genes are aggregated to signatures, and the downstream cell embedding. CIPHER integrates the physical limits of imaging assays directly into its loss function, shaping the latent space to maximize discriminability while maintaining robustness to measurement noise and signal constraints. Using a large-scale mouse brain scRNA-seq reference, we show that CIPHER-designed encodings yield latent spaces with improved cell-type separability, uniform signal utilization, and greater resilience to hybridization variability, resulting in higher decoding accuracy from both simulated and experimental data. Conclusion CIPHER formulates aggregate signature design as a joint optimization problem over decoding accuracy and experimental measurability. This enables systematic, scRNA-seq-aligned feature design for scalable spatial transcriptomics based on aggregate measurements. Availability Code and documentation are available at https://github.com/wollmanlab/Design/.

06.
arXiv (CS.CV) 2026-06-11

VL-DINO: Leveraging CLIP Vision-Language Knowledge for Open-Vocabulary Object Detectio

Vision-language models like CLIP can provide rich semantic priors for open-vocabulary object detection. However, jointly integrating both textual and visual knowledge into detection architectures remains challenging. In this paper, we propose VL-DINO, an open-vocabulary detector that enhances DINO through more effective exploitation of CLIP's vision-language knowledge. Specifically, a Query-guided Positive Sample Construction (QPSC) module is first developed to construct additional high-quality positive samples, enabling the vanilla DINO framework to better accommodate mixed training across heterogeneous data sources while providing more vision-language alignment signals, thereby incorporating richer textual knowledge during training. A Visual Semantic Encoder (VSE) module is then introduced to distill CLIP visual knowledge into backbone-extracted features, producing fused features for subsequent encoder refinement. Based on the fused features, an Object-Region Semantic Alignment (ORSA) module extracts object-centric region features and aligns them with the corresponding textual embeddings, further incorporating textual cues. In the zero-shot setting, VL-DINO-T and VL-DINO-L achieve 36.3 and 38.1 AP on the LVIS benchmark, respectively, consistently outperforming prior advanced approaches. Extensive experiments demonstrate the effectiveness and competitive performance of the proposed design.

07.
arXiv (CS.LG) 2026-06-16

Conditional Score-Based Modeling of Effective Langevin Dynamics

arXiv:2604.23952v2 Announce Type: replace-cross Abstract: Stochastic reduced-order models are widely used to represent the effective dynamics of complex systems, but estimating their drift and diffusion coefficients from data remains challenging. Standard approaches often rely on short-time trajectory increments, state-space partitioning, or repeated simulation of candidate models, which become unreliable or computationally expensive for high-dimensional systems, coarse temporal sampling, or unevenly sampled data. We introduce a data-driven calibration method based on a novel relationship between the coefficients of a stochastic reduced model and the conditional score of the finite-time transition density, defined as the gradient of the logarithm of the transition density with respect to the initial state. The resulting identity expresses derivatives of lagged correlation functions as stationary expectations over observed lagged pairs involving this conditional score and the unknown model coefficients. This formulation allows the drift and diffusion structure to be constrained directly from finite-lag statistics, without differentiating trajectories, partitioning state space, or repeatedly integrating candidate reduced models during calibration, yielding a least-squares fitting problem over stationary lagged pairs. We validate the approach on three systems of increasing complexity: an analytically tractable Cox–Ingersoll–Ross diffusion, a two-dimensional nonequilibrium diffusion with affine multiplicative noise, and a periodic soft-spin stochastic Landau–Lifshitz chain. Across these tests, the inferred models preserve the invariant statistics while reproducing finite-lag dynamical correlations. The framework provides a scalable route for learning stochastic reduced-order models from data that reproduce prescribed statistical and dynamical properties.

08.
arXiv (CS.AI) 2026-06-24

Sensing Intelligence as a Trainable Metamaterial Property

arXiv:2605.23967v2 Announce Type: replace-cross Abstract: In biological systems, sensing is not performed by the brain alone: the body deforms, vibrates, and filters external stimuli before they are transduced into neural signals. In engineered systems, this processing burden is placed largely on electronics and computation, while the mechanical body is usually designed only for strength and stability. Here, we present sensing intelligence as a trainable property of the body. We show that the geometry of a metamaterial can be optimized to reshape external stimuli into internal signals that are easier for a neural network to interpret. Rather than hand-designing this physical preprocessing, we let the neural network train its own body for sensing by backpropagating the sensing loss to the body's design parameters through differentiable simulation. Across numerical and experimental sensing scenarios, the optimized body improves sensing accuracy by up to fivefold or reduces the number of required electronic sensors by nearly an order of magnitude.

09.
arXiv (CS.CL) 2026-06-18

Trade-offs in Medical LLM Adaptation: An Empirical Study in French QA

The development of large language models (LLMs) has led to an increased focus on their adaptation to specialized domains and languages, yet the effectiveness of domain adaptation strategies remains unclear. We present a study of medical domain adaptation using French medical question-answering (QA) as a case study. We compare continual pretraining (CPT), supervised fine-tuning (SFT), and their combination across three model families, multiple sizes, and three initialization types, explicitly disentangling adaptation effects from base model choice. We evaluate both multiple-choice (MCQA) and open-ended QA (OEQA) under greedy and constrained decoding using automatic metrics and LLM-as-a-Judge evaluation. For MCQA, CPT+SFT most often achieves the best scores, but gains over SFT are small and frequently not statistically significant, making SFT a strong and cost-effective default. For OEQA, CPT consistently improves overlap-based metrics, while SFT often degrades generation quality; instruction tuning and CPT+SFT are preferred by LLM-based evaluation. Cross-lingual experiments further show effective transfer from French adaptation to English benchmarks. Overall, we provide practical guidelines for selecting adaptation strategies under computational constraints.

10.
arXiv (CS.AI) 2026-06-16

Phys-JEPA: Physics-Informed Latent World Models for Multivariate Time-Series Forecasting

arXiv:2606.16076v1 Announce Type: cross Abstract: Multivariate forecasting in physical systems requires models that predict coupled temporal variables while preserving meaningful state evolution. Deep forecasters can fit temporal correlations, and physics-informed models can regularize predictions with scientific constraints, but these directions are often connected only at the decoded-output level. As a result, the hidden predictive state that generates future trajectories may remain statistically useful but physically unstructured. We introduce Phys-JEPA, a physics-informed joint-embedding predictive architecture for multivariate time-series forecasting. Phys-JEPA learns a latent world model in which predictive states are decomposed into physical and residual components, and physical consistency is imposed directly on latent states and latent transitions rather than only on decoded forecasts. This formulation uses known physical variables to organize the representation space while retaining residual capacity for unresolved dynamics. On Jena Climate 2009–2016, Phys-JEPA reduces aggregate MSE from 0.12482 to 0.12273 and temperature MSE from 0.01892 to 0.01831 at H=24. On Traffic, full Phys-JEPA improves aggregate MSE over the supervised baseline across all tested horizons, reducing H=192 MSE from 0.800784 to 0.773873. On Electricity, the best variant depends on horizon: static latent consistency is strongest at H=24 and H=48, while full Phys-JEPA gives the best aggregate and target-variable MSE at H=192. These initial results suggest that moving physics-informed learning from output space to latent predictive state space is a promising direction for interpretable temporal world models.

11.
arXiv (CS.CV) 2026-06-15

WAM4D: Fast 4D World Action Model via Spatial Register Tokens

World action models (WAMs) have recently shown promise in jointly modeling future observations and executable robot actions. However, most existing WAMs still operate in 2D video or latent spaces, where visually plausible rollouts miss the 3D spatial constraints and occluded contact geometry required for precise manipulation. While geometric foundation models offer strong priors for recovering dense 3D structure and motion from visual observations, forcing WAMs to predict the dense 4D representation introduces costly geometric decoding and slows down causal action generation. To address the trade-off, we present WAM4D, a fast 4D world action model that uses lightweight spatial register tokens as training-time future-depth readouts to transfer pretrained geometric priors into a causal video-action transformer, then removes the register branch for lightweight action inference. To prevent non-causal shortcuts, we further design causal mixture attention for the Mixture-of-Transformers (MoT) WAM backbone, defining modality-specific visibility among video, action, and geometry tokens. Comprehensive experiments on RoboTwin 2.0 and challenging real-world manipulation tasks show that WAM4D improves spatial consistency and achieves competitive action prediction while maintaining efficient inference.

12.
bioRxiv (Bioinfo) 2026-06-18

Deciphering shared and divergent tissue architectures from cross-species spatial transcriptomics

作者:

The integration of spatial transcriptomics (ST) data across species is essential for cross-species and translational studies, but remains challenging due to molecular divergence and anatomical differences between organisms. We present STACAME, a graph attention autoencoder-based framework to decipher shared and divergent tissue architectures from cross-species ST data by explicitly modeling both orthologous and species-specific genes. STACAME aligns ST slices in a spatially aware manner, identifies homologous and species-specific domains, and enables a suite of downstream comparative analyses. We demonstrate its utility by integrating ST datasets from diverse tissues, including hippocampus, isocortex, embryo, breast, liver, and cerebellum, across multiple species such as human, macaque, marmoset, mouse, and zebrafish. STACAME supports cross-species spatial domain alignment, the detection of shared and divergent spatially variable genes, development alignment and comparison, and the 3D integration of tissue architecture. This flexible approach facilitates the translation of findings from model organisms to humans, providing a unified computational platform for cross-species spatial transcriptomics.

13.
arXiv (CS.LG) 2026-06-16

From Physics to Representation: Audio Learning with Synthetic Pre-training via Procedural Generation

arXiv:2606.14791v1 Announce Type: cross Abstract: Self-supervised learning advances audio representation for multimedia analysis. However, prevailing data-centric approaches rely on massive real-world corpora, increasing training costs, curation burdens, and privacy barriers. To address this, we present AudioPG, a procedural synthesis framework eliminating real audio recordings during pre-training. AudioPG trains a Transformer-based masked autoencoder on waveforms generated on-the-fly from basic acoustic primitives and composition rules. The encoder transfers effectively to real audio benchmarks, achieving 90.60% accuracy on ESC-50, 0.546 mAP on FSD50K, 88.17% on UrbanSound8K, and 97.03% on Speech Commands V2. Notably, pre-training completes in under 20 minutes on a single GPU. Latent space analysis reveals physical factors, including fundamental frequency and relative intensity, emerge in orthogonal subspaces, making representations linearly decodable. These results establish procedural synthesis as an efficient, interpretable pre-training signal when large-scale corpora are unavailable. Our code is available at: https://github.com/Freyliu0516/audioPG.

14.
arXiv (CS.CL) 2026-06-24

Layer-wise Probing of wav2vec 2.0 and Whisper for Consonant Cluster Reduction in African American English

Self-supervised and supervised speech models are increasingly used to investigate which linguistic information their internal representations encode, and at what level of abstraction they encode it. One underexplored phenomenon is consonant cluster reduction (CCR) in African American English (AAE), a widespread phonological process and a source of automatic speech recognition (ASR) disparity. To examine how CCR is represented, we conduct speaker-independent layer-wise probing of wav2vec2-base and Whisper-small using two tasks: segmental reduction detection and segmental restoration of underlying cluster identity. Both models distinguish reduced and canonical forms with high accuracy. Crucially, reduced segments retain cues to their underlying stops, indicating that CCR is encoded as structured gradient phonological variation rather than simple segmental deletion. These results demonstrate structured phonological encoding of AAE CCR patterns in modern speech models.

15.
arXiv (CS.CV) 2026-06-17

Two-Stage Fine-Tuning of ResNet50 for High-Sensitivity Melanoma Detection on Dermoscopic Images

作者:

Melanoma is the most dangerous form of skin cancer with five-year survival rates exceeding 99% when detected early but falling sharply once the disease spreads. This paper proposes and evaluates a two-stage fine-tuning approach for ResNet50 applied to binary melanoma classification on dermoscopic images. The core challenges addressed are class imbalance and suboptimal transfer learning from single-stage fine-tuning. After stratified train/validation/test splitting, random oversampling was applied exclusively to the training set to achieve a 1:1 class balance. Stage 1 trained only the classification head with the ResNet50 base frozen, while Stage 2 fine-tuned all layers jointly at a low learning rate of 1e-5 to prevent catastrophic forgetting of learned visual features. On an independent test set of 3,826 images, the model achieved an AUC-ROC of 0.9559, accuracy of 88.34%, sensitivity of 87.56%, specificity of 89.13%, and F1-score of 88.29%. An ablation study confirms the two-stage protocol significantly outperforms single-stage fine-tuning, with sensitivity gains of over 4%. Grad-CAM visualizations demonstrate correct lesion localization. A fully deployable Streamlit detection application is provided alongside all training code.

16.
arXiv (CS.CV) 2026-06-16

Gen-VCoT: Generative Visual Chain-of-Thought Reasoning via Diffusion-Based RGB Intermediate Representations

Multimodal large language models (MLLMs) excel at visual reasoning but rely on text-based chain-of-thought (CoT), lacking interpretable visual intermediates. Existing methods use opaque tokens or external tools, missing key properties. We propose Gen-VCoT, a framework using expert vision models to generate RGB images as reasoning intermediates. It has three stages: visual grounding (SAM segmentation), geometric reasoning (Marigold depth maps), and semantic reasoning (Qwen2-VL integration). An adaptive router selects reasoning depth. Evaluations show Gen-VCoT improves spatial (25% better) and depth (50% better) questions, but may hurt simple factual queries. Text CoT outperforms visual intermediates on CLEVR (91.2% vs 62.5%), showing task-dependent optimal representations. Gen-VCoT establishes a new paradigm for interpretable multimodal reasoning.

17.
arXiv (CS.LG) 2026-06-19

Adversarial Bandit Optimization with Globally Bounded Perturbations to Convex Losses

arXiv:2606.19891v1 Announce Type: new Abstract: We study adversarial bandit optimization in which the loss functions may be non-convex and non-smooth. In each round, the learner selects an action and observes only the loss incurred at that action. The loss consists of an underlying convex and $\beta$-smooth component and an adversarial perturbation that may be chosen after observing the learner's action. The perturbations are subject to a global budget controlling their cumulative magnitude over time. This framework extends the globally budgeted, post-action perturbation model from underlying linear losses to general convex and $\beta$-smooth losses. For this broader class, we establish expected regret guarantees that explicitly characterize the effect of the perturbation budget. To establish these guarantees, we modify a standard bandit optimization algorithm and develop an analysis that controls the additional regret caused by the perturbations. In the absence of perturbations, our results reduce to regret guarantees for the standard bandit convex optimization setting with $\beta$-smooth losses.

18.
arXiv (CS.CL) 2026-06-11

Litespark Inference For CPUs: Ultra-Fast SIMD Framework for Ternary (1.58-bit) Language Models

Large language models (LLMs) have transformed artificial intelligence, but their computational requirements remain prohibitive for most users. Standard inference demands expensive datacenter GPUs or cloud API access, leaving over one billion personal computers underutilized for AI workloads. Ternary models offer a path forward: their weights are constrained to {-1, 0, +1}, theoretically eliminating the need for floating-point multiplication. However, existing frameworks fail to exploit this structure, treating ternary models as dense floating-point networks. We address this gap with custom SIMD kernels that replace matrix multiplication with simple addition and subtraction operations, targeting the integer dot product instructions available on modern CPUs. Our implementation, Litespark-Inference, is pip-installable and integrates directly with Hugging-Face, achieving 18.15x higher throughput, 7.15x faster time-to-first-token and 6.03x memory reduction compared to standard PyTorch inference on Apple Silicon, with comparable or higher throughput speedups up to 95.81x on Intel and AMD processors.

19.
arXiv (CS.CL) 2026-06-15

A Computational Audit of Demographic Association Encoding in ClinicalBERT Language Predictions

Transformer-based clinical language models are increasingly integrated into high-stakes clinical decision support pipelines, yet the computational mechanisms through which demographic associations encoded in medical documentation propagate into model probability distributions remain empirically underspecified. We present a systematic computational audit of representational bias in ClinicalBERT (Alsentzer et al., 2019), a BERT-based model pretrained on MIMIC-III discharge summaries, employing two complementary probing methodologies: Log Probability Bias Analysis (LPBA), which quantifies demographic descriptor-induced shifts in masked token probability distributions across behavioral and evaluative semantic categories, and Masked Language Model-based analysis (MLM), which probes internal representational structure for demographic agency attribution encoding across 98 real clinical sentence templates and eight intersectional race-gender combinations. Corpus frequency analysis operationalizes the distinction between statistical disparity and bias amplification by benchmarking model outputs against empirical term frequencies in the MIMIC-III training corpus. Of 32 statistically significant findings, 65.6% contradict observed corpus distributions, rising to 80% for Black patients and 87.5% for agency attribution under MLM probing, providing direct empirical evidence that representational bias in ClinicalBERT operates predominantly through model-internal amplification rather than training data inheritance. Keywords: natural language processing, clinical documentation, algorithmic auditing, representational bias, health equity 1

20.
arXiv (quant-ph) 2026-06-16

Minimum measurements quantum protocol for band structure calculation

arXiv:2511.04389v2 Announce Type: replace Abstract: Protocols for quantum measurement are an essential part of quantum computing. Measurements are no longer confined to the final step of computation but are increasingly embedded within quantum circuits as integral components of noise-resilient algorithms. However, each observable typically requires a distinct measurement basis, often demanding a different circuit configuration. As the number of such configurations typically grows with the number of qubits, measurements constitute a major bottleneck. Focusing on electronic structure calculations in crystalline systems, we propose a measurement protocol that restricts the required measurement configurations to an absolute minimum of just three, independent of the number of qubits. This makes it one of the few known protocols that do not scale with qubit number. In particular, we derive the measurement protocol from the symmetries of tight-binding (TB) Hamiltonians and implement it within the Orthogonal-Ansatz Variational Quantum Eigensolver (OA-VQE) algorithm. We demonstrate its performance on three systems, namely a two-dimensional CuO$_2$ square lattice (3 qubits), bilayer graphene with hexagonal (Honeycomb) lattice (4 qubits) and three-dimensional diamond lattice (10 qubits). Beyond tight-binding systems, the protocol can be extended to enable efficient initial state preparation for many-body Hamiltonians, such as multi-orbital Hubbard models in a momentum space.

21.
arXiv (CS.CV) 2026-06-11

Semantic Segmentation of Node and Edge Diagrams for Assistive Technology

In this paper, we present a novel set of related models for semantic segmentation of node-link diagrams. These diagrams are frequently used to represent mathematical graphs, relationships between concepts, and flowcharts. Such diagrams are difficult to access non-visually; while some assistive interfaces have been designed for node-link diagrams, they rely upon a machine-readable representation of the diagram, whereas such diagrams will generally be made available as bitmap images. Our compact deep learning models show excellent quantitative and qualitative performance on a large synthetic dataset of node-link diagrams, reaching per-pixel accuracy over 93\%.

22.
arXiv (CS.LG) 2026-06-11

Time-multiplexed layer reuse for physical neural networks

arXiv:2511.00044v3 Announce Type: replace Abstract: Physical neural networks (PNNs) are promising candidates for next-generation computing, but existing demonstrations remain several orders of magnitude smaller than modern digital neural networks, whose recent advances have been driven by rapid growth in trainable parameters. This situation resembles the constraints of early digital neural networks, which led to ideas around parameter reuse. We investigate what similarly efficient hardware architectures may look like, focusing specifically on the common bottleneck of slow re-adjustment of the weights in PNNs. We propose the Time-Indexed Deep Alternating Layers Network (TIDAL-Net), which occupies an intermediate regime between recurrent and deep neural networks, specifically aimed at the scales and restrictions of common PNN prototypes. TIDAL-Net leverages the timescale separation found in many PNNs between fast forward dynamics and slowly trainable weights and biases, using layer-by-layer time multiplexing to increase effective depth while limiting implementation cost. Numerical experiments on image classification and natural language processing tasks show that TIDAL-Net improves performance with only minor modifications to conventional PNNs.

23.
arXiv (CS.LG) 2026-06-25

Approximating velocity fields with planted attractors via Neural-ODEs for classification purposes

arXiv:2606.23550v2 Announce Type: replace-cross Abstract: In this work, Neural ODEs equipped with a curated collection of equilibrium points have been successfully employed for classification tasks. The planted attractors serve as indicators for the target classes, while the velocity field leveraging the universal approximation capabilities of the architecture shapes the dynamical landscape. This process defines the basins of attraction of the trained model, effectively directing each input (provided as an initial condition) toward its corresponding destination target.

25.
arXiv (CS.LG) 2026-06-18

Unraveling the Mechanism of Drug Binding to SARS-CoV-2 RNA Pseudoknot with Thermodynamics-Driven Machine Learning

arXiv:2604.14906v3 Announce Type: replace-cross Abstract: The pseudoknot secondary structure in SARS-CoV-2 RNA is essential for regulating protein synthesis through $-$1 programmed ribosomal frameshifting ($-1$ PRF), a mechanism that allows the virus to generate both structural and non-structural proteins from overlapping reading frames. This pseudoknot exhibits both threaded and unthreaded long-lived topologies. The influence of ligand binding on its folding is a process critical for the development of $-$1 PRF small-molecule inhibitors. Understanding this process through unbiased molecular dynamics (MD) simulations can be facilitated by introducing collective variables (CVs) that capture the corresponding slowest dynamical modes. Here, we use spectral map (SM), a thermodynamics-driven machine learning technique, to learn such CVs directly from all-atom MD trajectories of the SARS-CoV-2 RNA pseudoknot in complex with the $-$1 PRF inhibitor merafloxacin and its two structural analogs in neutral and ionized forms. Free-energy landscapes (FELs) derived from the learned CVs indicate that ligand-induced destabilization is topology-selective. In the threaded pseudoknot, the inhibitors destabilize the S2 stem, while in the unthreaded pseudoknot, destabilization occurs in the S1 and S3 stems. Furthermore, the extent to which each ligand reshapes the FEL matches experimentally reported antiviral potency, whereas the protonation state qualitatively alters dynamics within the same RNA topology. Overall, our results show how pseudoknot topology, ligand type, and protonation state collectively influence the slow conformational dynamics of viral RNA and establish physiological protonation as a critical factor for modeling RNA-targeted drug action.