arXiv subjects

Olexandr Isayev

Publications and source records attributed to Olexandr Isayev.

At least 19 recordsLinked to original sources

arXiv2026

MolecularCanvas: LLM-assisted Small-Molecule Drug Discovery via Structure-Guided Constraints

Small-molecule drug discovery relies on iterative molecular optimization, where chemists repeatedly modify candidate compounds to balance multiple competing properties such as efficacy, toxicity, and solubility. Recent advances in generative AI (GenAI) have shown promise in accelerating this process by automatically proposing new molecular structures or targeted modifications. However, existing GenAI-based molecular design tools remain poorly aligned with experts' real-world workflows. Specifically, they offer limited support for specifying structure-level modification intents on molecules, provide insufficient transparency into model-generated modifications, and lack integrated support for downstream property evaluation with external computational tools. To address these challenges, we introduce MolecularCanvas, an interactive system that enables users to iteratively construct an optimization context by integrating high-level goals, structure-level annotations, property constraints, and reference-based preferences. This context guides the generation of candidate molecules across diverse molecular structures. MolecularCanvas further enhances transparency by providing evidence for AI-generated suggestions and streamlines molecular evaluation by integrating commonly used computational tools for property assessment into a unified interface. Finally, a user study with 12 participants demonstrates the usefulness and effectiveness of MolecularCanvas in helping users optimize candidate molecules.

cs.HC↗

arXiv2026

CLORE: Content-Level Optimization for Reasoning Efficiency

Reinforcement learning post-training has improved the reasoning ability of large language models, but often produces unnecessarily long, repetitive, or semantically opaque reasoning traces. Existing efficient reasoning methods mainly regulate response length through explicit budgets or length-aware rewards, leaving intermediate reasoning content weakly supervised. We propose CLORE, a content-level optimization framework that improves reasoning efficiency by editing correct on-policy rollouts. CLORE uses an external augmentation model to delete repetitive segments, illegible or task-irrelevant content, and superfluous reasoning after the solution is established, while preserving the final answer. The resulting augmented--original pairs are optimized with an auxiliary reference-free DPO objective alongside standard policy-gradient training. By restricting augmentation to correct trajectories and performing local deletion, CLORE keeps edited rollouts close to the policy distribution and mitigates off-policy mismatch. Experiments on DeepSeek-R1-Distill-Qwen-7B and Qwen2.5-Math-7B across five mathematical reasoning benchmarks show that CLORE improves the accuracy--efficiency trade-off and remains compatible with GRPO, DAPO, Training Efficient, and ThinkPrune. Content-level analyses further show that CLORE reduces repetitive reasoning, illegible content, and post-answer exploration, supporting content-level supervision as a complementary direction to length-level control.

cs.AI↗

arXiv2026

Can Agents Price a Reaction? Evaluating LLMs on Chemical Cost Reasoning

Large Language Models (LLMs) have become increasingly capable as tool-using agents, with benchmarks spanning diverse general agentic tasks. Yet rigorous evaluation of scientific tool use remains limited. In chemistry, recent agents can plan syntheses and invoke domain-specific tools, but evaluations often rely on curated demonstrations, expert assessment, or LLM-as-judge scoring rather than exact, judge-free ground truth. We address this gap with chemical procurement cost estimation, a practical task in which an agent must ground chemical identities, retrieve supplier quotes, select valid purchasable packs, normalize quantities, and compute cost from a reaction description. We introduce ChemCost, a benchmark of 1,427 evaluable reactions grounded to a frozen pricing snapshot covering 2,261 chemicals and 230,775 supplier quotes, supporting scalar scoring and stage-level diagnosis of grounding, retrieval, procurement, and arithmetic failures. To evaluate robustness, we further construct controlled noise-injected views that perturb chemical aliases, quantity expressions, missing fields, and input formatting. Experiments with frontier, open-weight, and chemistry-specialized LLM agents show that tool access is necessary but insufficient for solving the task. The strongest agents reach only 50.6% accuracy within 25% relative error on clean inputs and degrade substantially with realistic noise. Stage-level analysis further shows that failures arise from brittle parsing, ineffective evidence integration, invalid pack selection, and non-convergent tool use.

cs.AI↗

arXiv2026

Knowing when to trust machine-learned interatomic potentials

Prevailing machine-learned interatomic potential (MLIP) uncertainty-quantification methods rely on ensembles of independently trained backbones. These methods scale unfavorably with foundation-scale MLIPs, and their member-disagreement signals correlate weakly with per-molecule prediction error. Here we probe the frozen per-atom representations of a pretrained MLIP with a compact discriminative classifier, recasting MLIP uncertainty quantification as selective classification rather than error regression. The resulting method, PROBE (Post-hoc Reliability frOm Backbone Embeddings), produces a per-prediction reliability probability that monotonically tracks actual error without modification to the underlying model. Across large held-out evaluation sets and two structurally distinct MLIP architectures, PROBE outperforms ensemble disagreement as a binary reliability signal, which strengthens with the expressiveness of the backbone representation, implying a favorable scaling trajectory toward foundation-scale MLIPs. Multi-head self-attention additionally yields per-atom importance maps, providing chemically interpretable diagnostics at no additional computational cost. PROBE is post-hoc and architecture-agnostic, and is directly deployable on any MLIP that exposes per-atom representations.

cs.LG↗

arXiv2026

KARA: Efficient Reasoning LLM Serving via Sliding-Window KV Cache Compression

Reasoning language models often generate long chain-of-thought (CoT), which accumulates a massive KV cache during the decoding phase and incurs high decoding latency and limited throughput. To address these issues, KV cache compression has emerged as a promising technique for reducing memory overhead by selectively removing unimportant KV pairs while preserving useful ones for subsequent decoding. Nevertheless, we identify two key limitations in existing KV cache compression methods: 1) their threshold-triggered compression policy may provide limited throughput improvement or even reduce throughput, and may fully eliminate KV pairs from certain blocks of the sequence, potentially worsening information loss. 2) they typically retain either isolated KV pairs or fixed-size chunks with rigid boundaries, failing to preserve important flexible-sized chunks at arbitrary token positions. To overcome these limitations, we propose Kara, a sliding-window KV cache compression method that performs decoding-time compression by operating only on the recently generated context. Kara leverages bidirectional attention to score and select informative KV pairs in the window. To enable flexible preservation of important semantic information, we design a Token2Chunk module to expand a subset of selected KV pairs into chunks. Furthermore, we adapt Kara to PagedAttention and develop KvLLM, an inference framework built upon vLLM, which reduces KV cache memory usage and effectively improves output throughput. Extensive experiments demonstrate consistent performance improvements of proposed Kara and KvLLM.

cs.CL↗

arXiv2025

Kolmogorov-Arnold Networks in Thermoelectric Materials Design

The discovery of high-performance thermoelectric materials requires models that are both accurate and interpretable. Traditional machine learning approaches, while effective at property prediction, often act as black boxes and provide limited physical insight. In this work, we introduce Kolmogorov--Arnold Networks (KANs) for the prediction of thermoelectric properties, focusing on the Seebeck coefficient and band gap. Compared to multilayer perceptrons (MLPs), KANs achieve comparable predictive accuracy while offering explicit symbolic representations of structure--property relationships. This dual capability enables both reliable predictions and the extraction of physically meaningful functional forms. Benchmarking against literature models further highlights the robustness and generalisability of the approach. Our findings demonstrate that KANs provide a powerful framework for reverse engineering materials with targeted thermoelectric properties, bridging the gap between predictive performance and scientific interpretability.

cond-mat.mtrl-sci↗

arXiv2025

The Future of Artificial Intelligence and the Mathematical and Physical Sciences (AI+MPS)

This community paper developed out of the NSF Workshop on the Future of Artificial Intelligence (AI) and the Mathematical and Physics Sciences (MPS), which was held in March 2025 with the goal of understanding how the MPS domains (Astronomy, Chemistry, Materials Research, Mathematical Sciences, and Physics) can best capitalize on, and contribute to, the future of AI. We present here a summary and snapshot of the MPS community's perspective, as of Spring/Summer 2025, in a rapidly developing field. The link between AI and MPS is becoming increasingly inextricable; now is a crucial moment to strengthen the link between AI and Science by pursuing a strategy that proactively and thoughtfully leverages the potential of AI for scientific discovery and optimizes opportunities to impact the development of AI by applying concepts from fundamental science. To achieve this, we propose activities and strategic priorities that: (1) enable AI+MPS research in both directions; (2) build up an interdisciplinary community of AI+MPS researchers; and (3) foster education and workforce development in AI for MPS researchers and students. We conclude with a summary of suggested priorities for funding agencies, educational institutions, and individual researchers to help position the MPS community to be a leader in, and take full advantage of, the transformative potential of AI+MPS.

cs.AI↗

arXiv2025

MolErr2Fix: Benchmarking LLM Trustworthiness in Chemistry via Modular Error Detection, Localization, Explanation, and Revision

Large Language Models (LLMs) have shown growing potential in molecular sciences, but they often produce chemically inaccurate descriptions and struggle to recognize or justify potential errors. This raises important concerns about their robustness and reliability in scientific applications. To support more rigorous evaluation of LLMs in chemical reasoning, we present the MolErr2Fix benchmark, designed to assess LLMs on error detection and correction in molecular descriptions. Unlike existing benchmarks focused on molecule-to-text generation or property prediction, MolErr2Fix emphasizes fine-grained chemical understanding. It tasks LLMs with identifying, localizing, explaining, and revising potential structural and semantic errors in molecular descriptions. Specifically, MolErr2Fix consists of 1,193 fine-grained annotated error instances. Each instance contains quadruple annotations, i.e,. (error type, span location, the explanation, and the correction). These tasks are intended to reflect the types of reasoning and verification required in real-world chemical communication. Evaluations of current state-of-the-art LLMs reveal notable performance gaps, underscoring the need for more robust chemical reasoning capabilities. MolErr2Fix provides a focused benchmark for evaluating such capabilities and aims to support progress toward more reliable and chemically informed language models. All annotations and an accompanying evaluation API will be publicly released to facilitate future research.

physics.chem-ph↗

arXiv2025

Anticipating the Selectivity of Intramolecular Cyclization Reaction Pathways with Neural Network Potentials

Reaction mechanism search tools have demonstrated the ability to provide insights into likely products and rate-limiting steps of reacting systems. However, reactions involving several concerted bond changes - as can be found in many key steps of natural product synthesis - can complicate the search process. To mitigate these complications, we present a mechanism search strategy particularly suited to help expedite exploration of an exemplary family of such complex reactions, cyclizations. We provide a cost-effective strategy for identifying relevant elementary reaction steps by combining graph-based enumeration schemes and machine learning techniques for intermediate filtering. Key to this approach is our use of a neural network potential (NNP), AIMNet2-rxn, for computational evaluation of each candidate reaction pathway. In this article, we evaluate the NNP's ability to estimate activation energies, demonstrate the correct anticipation of stereoselectivity, and recapitulate complex enabling steps in natural product synthesis.

cs.LG↗

arXiv2025

Applications of Modular Co-Design for De Novo 3D Molecule Generation

De novo 3D molecule generation is a pivotal task in drug discovery. However, many recent geometric generative models struggle to produce high-quality 3D structures, even if they maintain 2D validity and topological stability. To tackle this issue and enhance the learning of effective molecular generation dynamics, we present Megalodon-a family of scalable transformer models. These models are enhanced with basic equivariant layers and trained using a joint continuous and discrete denoising co-design objective. We assess Megalodon's performance on established molecule generation benchmarks and introduce new 3D structure benchmarks that evaluate a model's capability to generate realistic molecular structures, particularly focusing on energetics. We show that Megalodon achieves state-of-the-art results in 3D molecule generation, conditional structure generation, and structure energy benchmarks using diffusion and flow matching. Furthermore, doubling the number of parameters in Megalodon to 40M significantly enhances its performance, generating up to 49x more valid large molecules and achieving energy levels that are 2-10x lower than those of the best prior generative models.

cs.LG↗

arXiv2025

GEOM-Drugs Revisited: Toward More Chemically Accurate Benchmarks for 3D Molecule Generation

Deep generative models have shown significant promise in generating valid 3D molecular structures, with the GEOM-Drugs dataset serving as a key benchmark. However, current evaluation protocols suffer from critical flaws, including incorrect valency definitions, bugs in bond order calculations, and reliance on force fields inconsistent with the reference data. In this work, we revisit GEOM-Drugs and propose a corrected evaluation framework: we identify and fix issues in data preprocessing, construct chemically accurate valency tables, and introduce a GFN2-xTB-based geometry and energy benchmark. We retrain and re-evaluate several leading models under this framework, providing updated performance metrics and practical recommendations for future benchmarking. Our results underscore the need for chemically rigorous evaluation practices in 3D molecular generation. Our recommended evaluation methods and GEOM-Drugs processing scripts are available at https://github.com/isayevlab/geom-drugs-3dgen-evaluation.

cs.LG↗

arXiv2025

A practical guide to machine learning interatomic potentials -- Status and future

The rapid development and large body of literature on machine learning interatomic potentials (MLIPs) can make it difficult to know how to proceed for researchers who are not experts but wish to use these tools. The spirit of this review is to help such researchers by serving as a practical, accessible guide to the state-of-the-art in MLIPs. This review paper covers a broad range of topics related to MLIPs, including (i) central aspects of how and why MLIPs are enablers of many exciting advancements in molecular modeling, (ii) the main underpinnings of different types of MLIPs, including their basic structure and formalism, (iii) the potentially transformative impact of universal MLIPs for both organic and inorganic systems, including an overview of the most recent advances, capabilities, downsides, and potential applications of this nascent class of MLIPs, (iv) a practical guide for estimating and understanding the execution speed of MLIPs, including guidance for users based on hardware availability, type of MLIP used, and prospective simulation size and time, (v) a manual for what MLIP a user should choose for a given application by considering hardware resources, speed requirements, energy and force accuracy requirements, as well as guidance for choosing pre-trained potentials or fitting a new potential from scratch, (vi) discussion around MLIP infrastructure, including sources of training data, pre-trained potentials, and hardware resources for training, (vii) summary of some key limitations of present MLIPs and current approaches to mitigate such limitations, including methods of including long-range interactions, handling magnetic systems, and treatment of excited states, and finally (viii) we finish with some more speculative thoughts on what the future holds for the development and application of MLIPs over the next 3-10+ years.

cond-mat.mtrl-sci↗

arXiv2023

MLatom 3: Platform for machine learning-enhanced computational chemistry simulations and workflows

Machine learning (ML) is increasingly becoming a common tool in computational chemistry. At the same time, the rapid development of ML methods requires a flexible software framework for designing custom workflows. MLatom 3 is a program package designed to leverage the power of ML to enhance typical computational chemistry simulations and to create complex workflows. This open-source package provides plenty of choice to the users who can run simulations with the command line options, input files, or with scripts using MLatom as a Python package, both on their computers and on the online XACS cloud computing at XACScloud.com. Computational chemists can calculate energies and thermochemical properties, optimize geometries, run molecular and quantum dynamics, and simulate (ro)vibrational, one-photon UV/vis absorption, and two-photon absorption spectra with ML, quantum mechanical, and combined models. The users can choose from an extensive library of methods containing pre-trained ML models and quantum mechanical approximations such as AIQM1 approaching coupled-cluster accuracy. The developers can build their own models using various ML algorithms. The great flexibility of MLatom is largely due to the extensive use of the interfaces to many state-of-the-art software packages and libraries.

physics.chem-ph↗

arXiv2023

Learning Over Molecular Conformer Ensembles: Datasets and Benchmarks

Molecular Representation Learning (MRL) has proven impactful in numerous biochemical applications such as drug discovery and enzyme design. While Graph Neural Networks (GNNs) are effective at learning molecular representations from a 2D molecular graph or a single 3D structure, existing works often overlook the flexible nature of molecules, which continuously interconvert across conformations via chemical bond rotations and minor vibrational perturbations. To better account for molecular flexibility, some recent works formulate MRL as an ensemble learning problem, focusing on explicitly learning from a set of conformer structures. However, most of these studies have limited datasets, tasks, and models. In this work, we introduce the first MoleculAR Conformer Ensemble Learning (MARCEL) benchmark to thoroughly evaluate the potential of learning on conformer ensembles and suggest promising research directions. MARCEL includes four datasets covering diverse molecule- and reaction-level properties of chemically diverse molecules including organocatalysts and transition-metal catalysts, extending beyond the scope of common GNN benchmarks that are confined to drug-like molecules. In addition, we conduct a comprehensive empirical study, which benchmarks representative 1D, 2D, and 3D molecular representation learning models, along with two strategies that explicitly incorporate conformer ensembles into 3D MRL models. Our findings reveal that direct learning from an accessible conformer space can improve performance on a variety of tasks and models.

cs.LG↗

arXiv2023

Structure Prediction of Epitaxial Organic Interfaces with Ogre, Demonstrated for TCNQ on TTF

Highly ordered epitaxial interfaces between organic semiconductors are considered as a promising avenue for enhancing the performance of organic electronic devices including solar cells, light emitting diodes, and transistors, thanks to their well-controlled, uniform electronic properties and high carrier mobilities. Although the phenomenon of organic epitaxy has been known for decades, computational methods for structure prediction of epitaxial organic interfaces have lagged far behind the existing methods for their inorganic counterparts. We present a method for structure prediction of epitaxial organic interfaces based on lattice matching followed by surface matching, implemented in the open-source Python package, Ogre. The lattice matching step produces domain-matched interfaces, where commensurability is achieved with different integer multiples of the substrate and film unit cells. In the surface matching step, Bayesian optimization (BO) is used to find the interfacial distance and registry between the substrate and film. The BO objective function is based on dispersion corrected deep neural network interatomic potentials, shown to be in excellent agreement with density functional theory (DFT). The application of Ogre is demonstrated for an epitaxial interface of 7,7,8,8-tetracyanoquinodimethane (TCNQ) on tetrathiafulvalene (TTF), whose electronic structure has been probed by ultraviolet photoemission spectroscopy (UPS), but whose structure had been hitherto unknown [Organic Electronics 48, 371 (2017)]. We find that TCNQ(001) on top of TTF(100) is the most stable interface configuration, closely followed by TCNQ(010) on top of TTF(100). The density of states, calculated using DFT, is in excellent agreement with UPS, including the presence of an interface charge transfer state.

cond-mat.mtrl-sci↗

arXiv2022

Scalable Hybrid Deep Neural Networks/Polarizable Potentials Biomolecular Simulations including long-range effects

Deep-HP is a scalable extension of the \TinkerHP\ multi-GPUs molecular dynamics (MD) package enabling the use of Pytorch/TensorFlow Deep Neural Networks (DNNs) models. Deep-HP increases DNNs MD capabilities by orders of magnitude offering access to ns simulations for 100k-atom biosystems while offering the possibility of coupling DNNs to any classical (FFs) and many-body polarizable (PFFs) force fields. It allows therefore to introduce the ANI-2X/AMOEBA hybrid polarizable potential designed for ligand binding studies where solvent-solvent and solvent-solute interactions are computed with the AMOEBA PFF while solute-solute ones are computed by the ANI-2x DNN. ANI-2X/AMOEBA explicitly includes AMOEBA's physical long-range interactions via an efficient Particle Mesh Ewald implementation while preserving ANI-2X's solute short-range quantum mechanical accuracy. The DNNs/PFFs partition can be user-defined allowing for hybrid simulations to include biosimulation key ingredients such as polarizable solvents, polarizable counter ions, etc... ANI-2X/AMOEBA is accelerated using a multiple-timestep strategy focusing on the models contributions to low-frequency modes of nuclear forces. It primarily evaluates AMOEBA forces while including ANI-2x ones only via correction-steps resulting in an order of magnitude acceleration over standard Velocity Verlet integration. Simulating more than 10 $\mu$, we compute charged/uncharged ligands solvation free energies in 4 solvents, and absolute binding free energies of host-guest complexes from SAMPL challenges. ANI-2X/AMOEBA average errors are within chemical accuracy opening the path towards large-scale hybrid DNNs simulations, at force-field cost, in biophysics and drug discovery.

physics.chem-ph↗

arXiv2021

Simulation Intelligence: Towards a New Generation of Scientific Methods

The original "Seven Motifs" set forth a roadmap of essential methods for the field of scientific computing, where a motif is an algorithmic method that captures a pattern of computation and data movement. We present the "Nine Motifs of Simulation Intelligence", a roadmap for the development and integration of the essential algorithms necessary for a merger of scientific computing, scientific simulation, and artificial intelligence. We call this merger simulation intelligence (SI), for short. We argue the motifs of simulation intelligence are interconnected and interdependent, much like the components within the layers of an operating system. Using this metaphor, we explore the nature of each layer of the simulation intelligence operating system stack (SI-stack) and the motifs therein: (1) Multi-physics and multi-scale modeling; (2) Surrogate modeling and emulation; (3) Simulation-based inference; (4) Causal modeling and inference; (5) Agent-based modeling; (6) Probabilistic programming; (7) Differentiable programming; (8) Open-ended optimization; (9) Machine programming. We believe coordinated efforts between motifs offers immense opportunity to accelerate scientific discovery, from solving inverse problems in synthetic biology and climate science, to directing nuclear energy experiments and predicting emergent behavior in socioeconomic settings. We elaborate on each layer of the SI-stack, detailing the state-of-art methods, presenting examples to highlight challenges and opportunities, and advocating for specific ways to advance the motifs and the synergies from their combinations. Advancing and integrating these technologies can enable a robust and efficient hypothesis-simulation-analysis type of scientific method, which we introduce with several use-cases for human-machine teaming and automated science.

cs.AI↗

arXiv2020

Impressive computational acceleration by using machine learning for 2-dimensional super-lubricant materials discovery

The screening of novel materials is an important topic in the field of materials science. Although traditional computational modeling, especially first-principles approaches, is a very useful and accurate tool to predict the properties of novel materials, it still demands extensive and expensive state-of-the-art computational resources. Additionally, they can be often extremely time consuming. We describe a time and resource-efficient machine learning approach to create a large dataset of structural properties of van der Waals layered structures. In particular, we focus on the interlayer energy and the elastic constant of layered materials composed of two different 2-dimensional (2D) structures, that are important for novel solid lubricant and super-lubricant materials. We show that machine learning models can recapitulate results of computationally expansive approaches (i.e. density functional theory) with high accuracy.

physics.comp-ph↗