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01.
arXiv (CS.CL) 2026-06-11

When Generic Prompt Improvements Hurt: Evaluation-Driven Iteration for LLM Applications

Authors:

Evaluating Large Language Model (LLM) applications differs from conventional software testing because outputs are probabilistic, semantically variable, and sensitive to prompt and model changes. This technical report proposes the Minimum Viable Evaluation Suite (MVES), an audit-oriented structure for application-level LLM evaluation. MVES links application categories to failure modes, metrics, required artifacts, and validation evidence across general LLM applications, retrieval-augmented systems, and agentic workflows. We pair the framework with a reproducible local evaluation harness covering structured extraction, RAG citation/content-compliance, and instruction-following checks. Using Ollama with Llama 3 8B Instruct and Qwen 2.5 7B Instruct, we evaluate five prompt conditions over expanded 30-case-per-suite ablations. The results show that, in the tested local conditions, generic prompt additions do not produce monotonic improvements: stronger output-contract prompts improve strict extraction for both models, while RAG citation/content-compliance declines under some generic-rule conditions. The largest observed decline occurs for Qwen 2.5 on RAG when generic rules are appended to the user prompt, from 26/30 to 9/30. These findings support evaluation-driven prompt iteration: prompt changes should be treated as potential regression risks and tested against task-specific suites before deployment. The accompanying repository contains the test suites, prompt variants, evaluation harness, raw result logs, and scripts needed to reproduce the reported local ablations.

03.
arXiv (CS.CL) 2026-06-11

Beyond Fully Random Masking: Attention-Guided Denoising and Optimization for Diffusion Language Models

Diffusion large language models (dLLMs) offer an efficient alternative to autoregressive models through parallel decoding, yet existing post-training methods largely rely on random masking strategies that overlook intrinsic token dependencies. In this work, we present an empirical analysis of attention in dLLMs and show that tokens attending more strongly to unmasked context exhibit greater generation stability and play a critical role in reasoning. Motivated by these findings, we propose AGDO, an attention-guided denoising and optimization framework that aligns both training and optimization with attention-derived dependencies. AGDO determines the denoising order based on attention structure and emphasizes attention-critical tokens during supervised fine-tuning and reinforcement learning. Experiments on mathematical and coding benchmarks demonstrate that AGDO consistently improves reasoning performance, outperforming state-of-the-art post-training methods for dLLMs.

04.
arXiv (CS.AI) 2026-06-11

Towards Responsibly Non-Compliant Machines

arXiv:2606.12147v1 Announce Type: new Abstract: We consider the problem of engineering autonomous intelligent agents that are capable to responsibly not comply with user requests. We argue that machine non-compliance comes in many different forms, and sketch the issues we should pursue on the road of accomplishing responsibly non-compliant intelligent machines. We anchor responsible non-compliance in justifications for task refusal, pathways to override the non-compliance, as well as careful tracking of security risks and liability transfers.

05.
arXiv (CS.LG) 2026-06-19

Compositionality Emerges in a Narrow Depth-Connectivity Regime: Architecture Constraints and Solution Manifolds

arXiv:2606.19941v1 Announce Type: new Abstract: Compositionality is believed to be the foundation for generalization, enabling models to reuse meaningful primitives in novel combinations. Yet, models trained with standard gradient-based optimization rarely, and often only weakly, exhibit compositional internal structure, and it remains unclear how or why such compositionality forms. In this work, we show that compositionality emerges in a narrow connectivity-depth sweet spot. Along the connectivity axis, compositionality only appears in some specifically sparse networks, heavily depends on which connections remain rather than on weights' sparsity alone. Along the depth axis, compositionality emerges within a narrow, target-dependent regime, peaking at specific depths, while both shallower and deeper networks fail. When either the depth or connectivity condition is violated, gradient descent silently converges to fractured solutions rather than compositional ones. To discover and exploit this emergence, we introduce (i) similarity-based pruning (SP) to recover compositional connectivity and (ii) a heuristic depth predictor to estimate where compositionality is most likely to appear. Finally, we support these empirical findings with a theoretical framework based on compositional sparsity, volume-ratio arguments, and feature-interference bounds, explaining why compositional solutions are reachable only in a narrow depth-connectivity regime.

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

Closing the Social-Semantic Gap: SPSD for Edge-Based Prompt Compression in Cloud LLM Inference

arXiv:2606.19364v1 Announce Type: new Abstract: The prefill stage of Large Language Model (LLM) inference is a growing contributor to cloud-scale energy cost. Many consumer-support and conversational prompts contain social scaffolding: politeness markers, apologetic preamble, repetition, and rapport-building language that is important for human communication but carries low marginal information for machine reasoning. We call this discrepancy the Social-Semantic Gap. We present SPSD (Sentiment Preserving Semantic Distillation), an edge-based pipeline that compresses user prompts using a 4-bit quantised Small Language Model before transmission to a cloud-deployed LLM. Evaluation on a 248-prompt corpus using Gemma-2-2B-Instruct (Q4_K_M) as the SLM and Llama-3.1-8B-Instruct as the cloud evaluation model yields a mean input token saving of 99.9 tokens per distilled call, with all 146 distilled calls yielding positive savings. Response quality, assessed by blind LLM-as-judge scoring across 121 pairs, is non-inferior to the raw path within a pre-specified 1-point margin on a 15-point rubric; the judge awarded 43 percent ties, 28 percent distilled wins, and 29 percent raw wins. Cosine similarity is mixed: mean 0.682, median 0.712, with 54.1 percent of pairs above the 0.70 reference threshold. Safety-critical domains are conservatively routed to passthrough via rule-based gates. Per-call net energy saving is estimated at 70-270 uWh under stated assumptions. SPSD shows that on-device prompt distillation can reduce cloud LLM input-token cost while preserving response quality within a practical non-inferiority margin.

07.
arXiv (quant-ph) 2026-06-17

An energy-based uncertainty principle and low-energy state preparation

Authors:

arXiv:2603.15495v2 Announce Type: replace Abstract: Preparing low-energy states of many-body Hamiltonians is a central challenge in quantum computing, quantum complexity, and condensed matter physics. Existing approaches often get trapped in suboptimal states such as high-energy eigenstates or, more generally, low-variance states that resist further energy reduction. In this work, we explore a different perspective: instead of optimizing with respect to a single Hamiltonian, we leverage the fact that many systems admit families of Hamiltonians that share similar low-energy subspaces but differ at higher energies. We show that this redundancy can be turned into an algorithmic resource by establishing an energy-based uncertainty principle, which implies that these Hamiltonians cannot simultaneously admit low-variance states at higher energies. This suggests a simple strategy of alternating energy-lowering steps across such Hamiltonians, which we investigate numerically on several models. We also introduce a sparse variant where the uncertainty principle yields quadratically larger variance at higher energies, leading to more pronounced energy change. Overall, this work suggests a range of open questions at the interface of random matrix theory, local Hamiltonians and low-energy state preparation, aimed at understanding when such approaches are practical and how they can be analyzed rigorously.

08.
arXiv (CS.CL) 2026-06-19

Towards Truly Multilingual ASR: Generalizing Code-Switching ASR to Unseen Language Pairs

Automatic Speech Recognition (ASR) has become a key technology for human–AI interaction. However, code-switching ASR (CS-ASR) remains particularly challenging due to the severe scarcity of multilingual CS speech resources across diverse language pairs. Existing approaches primarily improve CS-ASR performance through synthetic CS speech generation or pair-specific fine-tuning on limited bilingual datasets. Nevertheless, these approaches face an inherent scalability limitation, as support for CS must be developed separately for language pairs whose number grows combinatorially with the number of supported languages. In this work, we investigate whether CS capabilities learned from a limited set of seen language pairs can generalize to unseen language pairs through model merging and domain generalization methods. Our experiments show that merged bilingual CS-ASR models modestly generalize to unseen language pairs, suggesting limited transfer of bilingual CS capabilities across language pairs.

09.
bioRxiv (Bioinfo) 2026-06-20

A network approach to DNA methylation clocks

Biological age predicts health and lifespan better than chronological age, but remains difficult to measure. One leading molecular proxy for biological age is DNA methylation, which underlies age predictors known as "clocks". These clocks use penalized linear regression to predict chronological age from methylation levels using selected cytosine–guanine pairs (CpGs) along DNA. Although they predict chronological age within a few years and track mortality risk, there are several issues. Different clocks share a vanishingly small number of CpG sites, many of which show weak associations with age. Also, the clocks often do not transfer across methylation array platforms. This paper takes a network approach to better understand these issues. By using 12 public datasets from human blood, we build a co-methylation network of the sites that show the strongest age correlation. After pruning weak links, we find that it has a small number of large modules of covarying CpGs surrounded by many small modules and singleton sites. These modules are biologically interpretable, as they are associated with CpG island contexts and enriched for distinct Gene Ontology functions. We also map five established clocks onto this network (Horvath, Hannum, AltumAge, Skin & Blood, and Han) and find that they select some CpGs from the same module. This suggests that they are more similar than they appear. The network structure also suggests new ways to build clocks. A simple clock that retains one CpG per module matches the performance of established clocks. A second one, built from module-level principal components, outperforms all five established clocks in three validation cohorts and is transferable across array platforms (Illumina Infinium Methylation 450K or EPIC arrays). Overall, the network perspective shifts attention from individual CpG sites to modules of covarying sites. This perspective helps explain why DNA methylation clocks perform so well despite their differences and provides a more systematic approach for developing the next generation of aging biomarkers.

10.
arXiv (CS.AI) 2026-06-12

The KG-ER Conceptual Schema Language

arXiv:2508.02548v3 Announce Type: replace-cross Abstract: We propose KG-ER, a conceptual schema language for knowledge graphs that describes the structure of knowledge graphs independently of their representation (relational databases, property graphs, RDF) while helping to capture the semantics of the information stored in a knowledge graph.

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

ANSR-DT: A Neuro-Symbolic Framework for Adaptive and Explainable Digital Twins

arXiv:2501.08561v4 Announce Type: replace Abstract: Digital twins are increasingly used to monitor and optimize industrial systems, yet many existing frameworks remain difficult to interpret, slow to adapt, and limited in their ability to incorporate explicit domain knowledge. This paper presents ANSR-DT, an adaptive neuro-symbolic framework that unifies temporal anomaly detection, symbolic reasoning, and reinforcement-learning-based decision support within a single digital twin pipeline. ANSR-DT combines a CNN-LSTM model for multivariate pattern recognition with Prolog-based reasoning that converts learned signals into explicit rules, enabling transparent diagnoses and traceable decision paths. A PPO-based adaptation layer further refines operational responses under changing conditions while preserving interpretability. Experiments against 8 baselines show that ANSR-DT delivers competitive predictive performance together with stable rule extraction, scalable symbolic reasoning, and actionable explanations. Additional validation on the Skoltech Anomaly Benchmark (SKAB) further indicates that the framework transfers beyond synthetic settings. These findings position ANSR-DT as a practical foundation for trustworthy, adaptive, and explainable industrial digital twins.

12.
arXiv (quant-ph) 2026-06-15

An integrated ultrahigh vacuum cluster tool for diamond surface science and single nitrogen-vacancy center measurements

arXiv:2606.13961v1 Announce Type: new Abstract: We present a custom-designed ultrahigh vacuum (UHV) cluster tool developed for studying shallow nitrogen-vacancy (NV) centers in diamond, enabling in situ diamond surface preparation, characterization, and single NV center dynamics measurements within a single connected platform. The system combines a surface science chamber for controlled surface modification and analysis with a cryogenic confocal microscope chamber dedicated to NV spin and optical measurements. This integrated approach enables a direct correlation between diamond surface chemistry and the resulting NV spin and charge properties. The instrument provides a versatile platform for systematic studies of surface-induced decoherence mechanisms and charge dynamics for shallow NV centers, and establishes a pathway toward reproducible surface engineering for quantum sensing applications.

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

The limits of interpretability in multiple linear regression

arXiv:2606.16013v1 Announce Type: cross Abstract: Interpreting machine-learning models has attracted increasing attention, particularly in the physical sciences, where one often seeks to understand the underlying mechanisms rather than merely make predictions. Multiple linear regression is often regarded as an interpretable alternative to more complex models, such as deep neural networks, because its predictions are expressed as explicit weighted sums of input features. However, when input features are strongly correlated, namely in the presence of multicollinearity, the learned weights can exhibit large dataset-to-dataset fluctuations and oscillatory behavior across physically similar features, making their interpretation difficult or even impossible. Although the instability of the weights under multicollinearity is well known in statistics, its consequences for physical interpretation, in particular its connection to oscillatory weights across physically similar features, have not been systematically clarified. Here, we theoretically discuss the mechanism behind this loss of interpretability by analyzing the eigenmodes of the feature correlation matrix. We show that small-eigenvalue modes associated with multicollinearity amplify fluctuations in the weights and generate oscillatory patterns that do not necessarily reflect meaningful contributions. We test this theoretical picture numerically on physics datasets and show that Ridge regularization suppresses these unstable modes, although the resulting weights must still be interpreted with caution. We further confirm the generality of our findings beyond physics by analyzing a diverse collection of publicly available datasets. Our results clarify why, in the presence of multicollinearity, physical interpretation can remain difficult even for linear regression models.

14.
arXiv (CS.CV) 2026-06-17

Visuals Lie, Consistency Speaks: Disentangling Spatial Attention from Reliability in Vision-Language Models

Multimodal Foundation Models are increasingly used as reasoning agents, making reliability, knowing when a model may hallucinate, critical. A common intuition, which we call the Attention-Confidence Assumption, holds that reliability follows from "structural" visual perception: tight attention on relevant regions should signal a trustworthy answer, while scattered attention signals confusion. We challenge this through the VLM Reliability Probe (VRP), a systematic cross-family study of reliability signals in contemporary Vision-Language Models (VLMs). We introduce structural-attention metrics, cluster counts (C_k) and spatial entropy (H_s), to quantify the visual encoder's gaze, and track its evolution (Delta H_s) across layers. This reveals a "Symbolic Detachment": models often "Early Lock" visual features only to diffuse attention later, severing early perception from final generation. Contrary to the grounding hypothesis, we find a "Cluster Failure": spatial attention has near-zero correlation (R approx 0.001) with accuracy. Instead, reliability is a phenomenon of generation dynamics and internal-state distributions. Self-Consistency, the agreement rate across sampled reasoning paths, is the dominant predictor of truth (R = 0.429). Scaling causal interventions exposes a sharp architectural divergence: LLaVA locks its prediction in a fragile late-stage bottleneck, whereas PaliGemma and Qwen2-VL distribute reliability globally, staying resilient even when ~50% or more of their most predictive layer is destroyed. For current VLMs, reliability signals are detached from visual grounding maps and are best inferred from generation-time dynamics and hidden-state probes.

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

MeshFlow: Efficient Artistic Mesh Generation via MeshVAE and Flow-based Diffusion Transformer

We present MeshFlow, a new method for generating artist-like 3D meshes. Current mesh generators often adopt Auto-Regressive (AR) next-token prediction, a natural choice given the discrete nature of mesh topology. However, AR methods scale poorly because the inference cost is quadratic in mesh size. They also require discretizing the vertex coordinates, which introduces quantization errors. To address these challenges, we introduce a Variational Autoencoder (VAE) that, supervised with a contrastive loss, represents both continuous vertex positions and discrete connectivity in a continuous latent space. This latent space is significantly more compact than prior token-based mesh representations. We then build a 3D generator based on a Rectified Flow transformer, generating all mesh vertices and edges in parallel. Our model generates meshes 18x faster than the fastest AR generator while also achieving excellent accuracy across standard mesh-generation metrics. Homepage: https://mesh-flow.github.io/, Code: https://github.com/facebookresearch/meshflow

17.
arXiv (CS.AI) 2026-06-18

Vibe Coding Ate My Homework: An evaluation of AI approaches to greenfield software engineering and programming

arXiv:2606.18293v1 Announce Type: cross Abstract: Thanks to rapid developments in generative AI, we are in the midst of a paradigm shift that may change how we interact with computers forever. We have observed a growth in the use of natural language prompts to build applications and coding infrastructures without underlying knowledge of the field, and this practice has been dubbed `vibe coding.' It arguably represents what the field of programming has been building towards since the beginning, with every higher level of abstraction that is conceived. Vibe coding promises to be the endpoint for the meta of high-level programming as far as method of input is concerned: eliminating a human's use of code syntax entirely in favour of programming in their mother tongue. This paper aims to evaluate the viability of vibe coding for greenfield software engineering tasks, as well as analyse the benchmarks that have been used to measure its software engineering prowess. To this end, we have developed an evaluation suite for analysing an LLM's proficiency in carrying out simple, isolated greenfield programming tasks in Python to provide scoped insight on the matter.

18.
arXiv (CS.CL) 2026-06-15

OLaPh: Optimal Language Phonemizer

Phonemization is a critical component in text-to-speech synthesis. Traditional approaches rely on deterministic transformations and lexica, while neural methods offer potential for higher generalization on out-of-vocabulary (OOV) terms. We introduce OLaPh (Optimal Language Phonemizer), a hybrid framework that integrates extensive multilingual lexica with advanced NLP techniques and a statistical subword segmentation function. Evaluations on the WikiPron benchmark show OLaPh significantly outperforms established baselines in overall accuracy and maintains robustness on OOV data through advanced fallback mechanisms. To further explore neural generalization, we utilize the framework to synthesize a high-consistency training corpus for an instruction-tuned Large Language Model (LLM). While the deterministic framework remains more accurate overall, the LLM demonstrates strong generalization, matching or partly exceeding the framework's performance. This suggests that the LLM successfully internalized phonetic intuitions from the synthetic data that transcend the framework's capabilities. Together, these tools provide a comprehensive, open-source resource for multilingual grapheme-to-phoneme conversion (G2P) research.

19.
arXiv (CS.AI) 2026-06-18

Pareto Q-Learning with Reward Machines

arXiv:2606.19134v1 Announce Type: cross Abstract: We present Pareto Q-Learning with Reward Machines (PQLRM), a multi-objective reinforcement learning algorithm for tasks whose reward structure is specified by a set of reward machines (RMs). PQLRM combines Pareto Q-Learning (PQL), which maintains sets of vector-valued Q-estimates to approximate the Pareto front, with enhancements from Q-Learning with Reward Machines (QRM), which exploits the factored automaton structure of the reward signal. This yields a multi-policy algorithm that remains sample-efficient under non-Markovian, RM-encoded rewards. Experimental trials show that PQLRM converges faster than a naive PQL baseline applied to the cross-product MDP and can synthesize Pareto-optimal policies that QRM cannot.

20.
arXiv (CS.CL) 2026-06-17

Speaking in Self-Assessing Tongues: On the Verbalized Confidence of LLMs in Machine Translation

The rapid rise in popularity of large language models (LLMs) for translation calls for a thorough study of the reliability of their confidence in their own outputs. Unlike many generation tasks, translation errors and confidence levels can be useful at different levels of granularity (tokens, words, or spans). Unsupervised approaches based on internal signals like predicted probabilities can be misleading because they reflect certainty among alternatives rather than correctness. In addition, they require access to such internal signals. Here, we devise five verbalized methods of extracting an LLM's per-token confidence without those shortcomings and compare their reliability with that of the model's internal signals of certainty. We evaluate reliability using two forms of alignment: fine-grained error detection and calibration. For both, internal and verbalized methods perform similarly, although results vary by model. Interestingly, we find little to no correlation between internal and verbalized methods.

21.
arXiv (quant-ph) 2026-06-11

Unifying framework for quantum simulation algorithms for time-dependent Hamiltonian dynamics

arXiv:2411.03180v2 Announce Type: replace Abstract: Recently, there has been growing interest in simulating time-dependent Hamiltonians using quantum algorithms, driven by diverse applications, such as quantum adiabatic computing. While techniques for simulating time-independent Hamiltonian dynamics are well-established, time-dependent Hamiltonian dynamics is less explored and it is unclear how to systematically organize existing methods and to find new methods. Sambe-Howland's continuous clock elegantly transforms time-dependent Hamiltonian dynamics into time-independent Hamiltonian dynamics, which means that by taking different discretizations, existing methods for time-independent Hamiltonian dynamics can be exploited for time-dependent dynamics. In this work, we systemically investigate how Sambe-Howland's clock can serve as a unifying framework for simulating time-dependent Hamiltonian dynamics. Firstly, we demonstrate the versatility of this approach by showcasing its compatibility with analog quantum computing and digital quantum computing. Secondly, for digital quantum computers, we illustrate how this framework, combined with time-independent methods (e.g., product formulas, multi-product formulas, qDrift, and LCU-Taylor), can facilitate the development of efficient algorithms for simulating time-dependent dynamics. This framework allows us to (a) resolve the problem of finding minimum-gate time-dependent product formulas; (b) establish a unified picture of both Suzuki's and Huyghebaert and De Raedt's approaches; (c) generalize Huyghebaert and De Raedt's first and second-order formula to arbitrary orders; (d) answer an unsolved question in establishing time-dependent multi-product formulas; (e) and recover continuous qDrift on the same footing as time-independent qDrift. Thirdly, we demonstrate the efficacy of our newly developed higher-order Huyghebaert and De Raedt's algorithm through digital adiabatic simulation.

22.
arXiv (CS.AI) 2026-06-16

XFlow: An Executable Protocol Programming System for Reliable Multi-Agent Workflows

arXiv:2606.14790v1 Announce Type: cross Abstract: LLM-based multi-agent systems increasingly coordinate planning, reasoning, tool use, and human interaction, yet their reliability remains limited. A central source of this limitation is the underspecified prompt–harness boundary. Current systems lack a principled way to decide which workflow commitments should remain in prompts and which should become harness structure. We present XFlow, an executable protocol programming system for reliable multi-agent workflows, and XPF (XFlow Protocol Format), its domain-specific protocol programming language. XFlow occupies a middle position between prompt-only orchestration and markup-like workflow descriptions. XPF remains readable as a literate protocol, but it is compiled and executed as a program. Its design keeps informal semantic work inside actors while moving selected commitments into harness structure that can be checked, preserved, and enforced. At runtime, XFlow stages uncertainty through lifecycle-governed symbols, which are typed state cells with validation and commit states. Actor outputs are mediated before they become shared state, instead of spreading through prompts, transcripts, or implicit memory. Our experiments cover Constrained Interaction, Long-Context Reasoning, and Agentic Software Engineering. They show that XFlow improves reliability by making constraints, evidence handling, and process requirements explicit and enforceable.

23.
arXiv (CS.CL) 2026-06-16

P3B3: A Multi-Turn Conversational Benchmark for Measuring European and Brazilian Portuguese Variety Bias in LLMs

As Large Language Models (LLMs) become embedded in everyday communication, capturing regional linguistic variation is essential for reliable and equitable language use. In Portuguese, European (pt-PT) and Brazilian (pt-BR) varieties remain unevenly represented, with pt-BR dominating in data quantity, while LLM preference for Portuguese variants remains underexplored. To address this gap, we introduce P3B3, an expert-curated language variety agnostic benchmark of conversational prompts, along with an evaluation framework for measuring variety bias and controllability. Experiments on several models show that most LLMs exhibit a strong bias toward pt-BR, with variation in controllability across models. These results highlight the need for more balanced multilingual representation across language varieties.

24.
arXiv (CS.LG) 2026-06-12

GenAutoML: An Agentic Framework for Dynamic Architecture Generation and Optimization in Time-Series Analysis

arXiv:2606.05860v2 Announce Type: replace Abstract: Designing neural architectures for time-series forecasting and anomaly detection remains a resource-intensive task that often requires substantial domain expertise. Traditional Automated Machine Learning (AutoML) systems typically rely on static, predefined search spaces, limiting their ability to adapt to diverse data characteristics. We present GenAutoML, an agentic framework that leverages Large Language Models (LLMs) as neural architects to bridge natural-language requirements and executable PyTorch implementations. The framework incorporates a Sandboxed Reflection Loop for autonomous code refinement and a Signature-Aware Runtime that enforces architectural consistency and execution safety. To improve robustness under non-stationary conditions, we further introduce a Dynamic Reversible Instance Normalization (Dyn-RevIN) wrapper. Experiments on the ETTh1, ETTm1, and Weather benchmarks demonstrate that GenAutoML can dynamically generate task-specific neural architectures tailored to dataset characteristics. Among the generated models, WaveInterferenceNet achieves inference latency below 0.01 ms per sample while maintaining competitive predictive performance. By emphasizing computational efficiency, architectural adaptability, and stable optimization behavior, GenAutoML enables the creation of ultra-lightweight neural networks suitable for resource-constrained and latency-sensitive Edge AI deployments.

25.
bioRxiv (Bioinfo) 2026-06-16

DMcloud: Macromolecular Structure Modeling Using Local Structure Fitting for Medium to Low Resolution cryo-EM maps

Cryogenic electron microscopy (cryo-EM) has become an essential experimental approach in structural biology for determining macromolecular structures. When the resolution of a cryo-EM map is worse than approximately 5[A], fitting known or predicted molecular models into the map becomes a common strategy for interpretation. However, accurately fitting biomolecular models into cryo-EM maps, particularly for large macromolecular complexes, remains challenging when the input structure models contain errors or are in a conformation different from that represented in the map. Here, we present DMcloud, a method for local structure fitting of proteins and nucleic acids in cryo-EM maps. Instead of forcing an entire input model into the map, DMcloud divides input structures into local regions, identifies regions that are supported by the density, removes unsupported regions, and assembles the retained regions into a final model. We benchmarked DMcloud on 176 cryo-EM maps, including intermediate and high-resolution maps that include proteins, DNAs, or RNAs. For EM maps in the 5.0-10.0 [A] and 2.5-5.0 [A] resolution ranges, DMcloud achieved average sequence modeling coverage of 0.49 and 0.70, respectively. For DNA/RNA maps, DMcloud achieved an average sequence coverage of 0.75. Across all datasets, DMcloud consistently outperformed existing methods in model accuracy, map-model correlation, and modeling coverage.