Quantum hardware can provide feedback for training circuit generators beyond the reach of exact classical simulation. We train generative quantum eigensolver (GQE) policies, transformers conditioned on molecular descriptors, to generate the state-preparation circuits for sample-based quantum diagonalization (SQD). Training runs first on a noiseless simulator and then with the IBM Heron processor ibm_kobe inside the loop, at 46 and 70 qubits ($1.2 \times 10^8$ shots for the four main training runs). A classical CCSD(T) reference energy of the training molecules enters only an admission gate and two auxiliary reward terms. During hardware training, a reward penalty prevents collapse to circuits that sample only the Hartree-Fock determinant. Policies trained on transition-metal complexes are applied without retraining to Sn(OH)$_3$-Me and its hydrates, minimal models of organotin photoresists for extreme-ultraviolet lithography, from 32 to 70 qubits. After one round of hardware sampling, followed by classical ranking and recovery of the cached counts with the molecular Hamiltonian and no further QPU calls, 27 of 28 runs at 46-70 qubits are within 15 mHa of the density-matrix renormalization group (DMRG) reference (median 4.5 mHa), and in all eight runs with an untrained control the trained policy is more accurate. At 56-70 qubits the selected circuits use 34-72 times fewer two-qubit gates than the local unitary cluster Jastrow (LUCJ) circuit transpiled for the same device. These results demonstrate that circuit generators can be trained with quantum hardware at 70 qubits.
Coding agents built on large language models, run in automated improvement loops, can discover more efficient algorithms. We present AIOA, a framework that brings this approach to the numerical algorithms of atomistic simulation: an agent improves an algorithm against a pre-specified metric in a loop guarded by verifiers it cannot alter. Applied to ASE, a widely used atomistic simulation library, AIOA targets two facets of an algorithm: its implementation, rewritten to run faster with unchanged results, and the method itself, redesigned to converge with fewer force evaluations. Agents made six kernels 22-24 times faster on average in Python with NumPy and SciPy. On unseen problems, optimizers from the best configuration needed 3.1-3.4 times fewer force evaluations than L-BFGS for structure relaxation and 4.6-17 times fewer than standard climbing-image nudged elastic band calculations for reaction paths. The agents' optimizers also contain two algorithmic components we did not find in the literature.
Machine-learned circuit parameters could remove one of the main bottlenecks of variational quantum eigensolvers: the classical optimization loop, with its typical barren plateaus, local minima, and costly energy and gradient evaluations, is replaced by a direct prediction. Prior work showed that machine-learning models paired with a structured circuit design can transfer across system size and structure within hydrogenic systems. The next step: Extending them to organic molecules would seem to require re-training on use-case-specific training sets. In this work, we show that this is not necessary by establishing an alchemical approach. A geometric projection places surrogate hydrogen atoms along the bond directions of the target molecule and so maps its local bonding environment onto small hydrogenic fragments. Existing hydrogenic solvers can then be reused as they are. The only new quantity is a single projection radius per bond type, which is fitted once on a small reference molecule and reused unchanged thereafter. We demonstrate the approach on the separable-pair circuit designs that have been used in prior work and extend the approach to multi-circuit approaches that span effective bases for quantum subspaces.
Universal machine-learned interatomic potentials could make excited-state simulations across chemical space routine, but excitation energies, unlike ground-state energies, are not sums of atomic contributions. The excited states of noninteracting molecules are the union of their states, which pooled multistate readouts reproduce at best for the lowest state. We introduce LEH-MACE, whose excitation energies are the eigenvalues of a local excitation Hamiltonian assembled from atom-centred blocks, so this union holds exactly. We generated TD-DFT energies and forces for about 300,000 equilibrium, thermal, and excited-state geometries of over 100,000 molecules. LEH-MACE's advantage over direct readouts grew with the distance from the training data and was largest above $S_1$, with about half their $S_2$ and $S_3$ errors for long conjugated oligomers. For molecule pairs, only LEH-MACE kept its single-molecule accuracy, while a softmin readout remained superior for $S_1$ dynamics of larger chromophores. Exact size consistency is thus one step toward such potentials.
We prove universal approximation for the bilinear-readout equivariant message-passing network (BREMP), a reference architecture for equivariant graph neural network interatomic potentials. Its layers combine equivariant convolutions with affine maps, and its readout forms invariants from products of the equivariant features. We construct a one-layer feature that determines the local environment up to permutations of atoms of the same type. The construction uses spherical harmonic filters of degree no larger than the largest number of neighbors at a common distance from the center. Iterating the construction recovers the environment reachable in as many hops as there are layers, using the same bound on filter degrees at the layer cutoff. The readout approximates every continuous invariant function of the features uniformly on compact sets. Together these give universal approximation of atomic energies at a prescribed physical range using a shorter layer cutoff. We assume that, throughout the admissible class, message passing reaches all neighbors in each physical environment within a common number of layers. Finally, DPA4, an interatomic potential architecture in production use, inherits this result by approximating the BREMP layers constructed in the proof and realizing the bilinear readout.
Peptide sequence-property relationships are often highly non-linear, but can be learned with machine learning models and exploited for the design of new materials and bioactive compounds. Various methods based on transformer architectures have become available for molecular property predictions. These foundation models promise straightforward inference and prediction of properties of new materials through in-context learning. Benchmarks of individual model architectures exist, but a systematic comparison of various foundation models against classical baselines on similar datasets is lacking. Here, we provide a systematic evaluation of the predictive performance of various in-context learning strategies. We compare several large language models, tabular foundation models, and typed decision models against an XGBoost baseline. We evaluate predictive performance on binary and multiclass classification tasks on pH-dependent surface activ-ity, IR spectral signatures, self-assembly, and anti-cancer activities. Our results show that ICL is competitive, yet does not significantly outperform classical baselines, and performance varies between models and tasks. Our findings further suggest that language models use both in context examples and knowledge acquired during pretraining to infer properties of unseen samples. This finding indicates that pretrained models can leverage the existing literature for predictions, but may also bias their predictions towards established sequence-property relationships.
It is well established that molecular substructures can contribute unequally to chemical and physical properties, with specific motifs or side chains often playing dominant roles. Fragment-based representations have therefore emerged as an effective strategy for incorporating chemically meaningful inductive biases, as exemplified by molecular fingerprints and fragment-based attention mechanisms. However, many existing fragmentation-based machine learning methods rely on predefined chemical rules, which may yield suboptimal fragmentation for previously unseen or chemically unfamiliar structures and often overlook the importance of multiscale molecular representations. To address these limitations, we formulate molecular fragmentation as a radius-constrained optimization problem inspired by the k-center formulation, where the number of clusters is not fixed a priori but emerges from the specified radius, and propose a geometry-based fragmentation method that partitions arbitrary molecular or material structures using largely geometric information, without relying on predefined chemical fragmentation rules. The method provides flexible control over fragment size, enabling the construction of multiscale fragment representations for scale-adaptive modeling. Building on this framework, we develop a geometric fragment-based attention mechanism that integrates multiscale structural information and incorporate it into a multimodal machine learning model combining p-SMILES representations with three-dimensional (3D) conformational information. Experiments on a benchmark polymer dataset show that incorporating 3D conformational information improves prediction accuracy for several properties over models based exclusively on p-SMILES representations. Explainable artificial intelligence analyses further provide insights into the physical relevance of the learned representations.
Organic crystal structure prediction (CSP) is a requirement for computational modelling of organic solids, but traditionally costs several CPU-years per molecule. Generative models such as OXtal dramatically reduce this cost by sampling stable organic crystal structures directly. However, OXtal forgoes explicit lattice parametrization in favour of modelling large crops of the bulk material with expensive triangle layers, which can incur a computational cost of minutes per molecule. In this paper, we reduce this to seconds with Clari, a large-scale flow matching model that generates redundancy-free unit cells and replaces triangle layers with pair-bias attention. Clari requires only atom types and bonds as input and does not need an RDKit-sanitizable input molecule, which expands its applicability to challenging chemistries such as fullerenes, metal complexes, and atom clusters. We further ablate key design choices such as auxiliary losses, timestep distributions, noise priors, and self-conditioning. On OXtal's test sets, we surpass OXtal's solve rate while obtaining a speedup of 15-30$\times$. Because Clari also models explicit hydrogens, it supports inference-time scaling via direct energy ranking, without any decoration or relaxation step. When generating 150 crystals and selecting the top-30 by energy, we further improve solve rate while maintaining a speedup of 5-8$\times$. We also introduce the CSD Teaching Subset as a new test split of diverse and complex molecules for future benchmarking. Our contributions enable CSP within seconds, making large-scale virtual screening of organic solids practical. Code is available at https://github.com/the-matter-lab/clari.
Atomic properties such as partial charges or multipoles encode chemically meaningful information that can inform downstream molecular property prediction, but their evaluation as machine learning targets has been complicated by the absence of a principled out-of-distribution evaluation protocol at the atomic level. In this work, we propose a held-out evaluation protocol that clusters atomic environments by SOAP descriptors and computes metrics accounting only for cluster labels unseen during training. Following this procedure, we use 5$\times$5 cross-validation and Tukey's HSD to run a statistically rigorous comparison of E(3)-equivariant against non-equivariant, rotationally augmented models for predicting electron populations and multipoles of H, C, N, and O atoms. Building on our results, we introduce the Quantum Topological Neural Network (QT-Net), a rotationally augmented, non-equivariant graph neural network. We show that QT-Net can be used to infer properties of atoms in molecules from QM9 outside our training set, and that the atomic environments seen during training strongly affect the performance of molecular property prediction tasks. To further validate the framework, molecular dipole moments computed from QT-Net's per-atom outputs recover the ground-truth values reported in QM9. We release all code and data, including a JAX implementation of QT-Net.
Chemical reaction datasets such as USPTO suffer from substantial incompleteness, frequently missing byproducts, co-reactants, and stoichiometric coefficients. This limits their applicability and reliability in downstream applications. Here, we introduce CompleteRXN, a large-scale supervised benchmark for reaction completion under realistic missing-data conditions. We construct a dataset of aligned incomplete and atom-balanced reactions by mapping USPTO records to curated mechanistic reactions. We evaluate representative baselines, including a novel encoder-decoder reaction completion model with constrained decoding, the Constrained Reaction Balancer (CRB), and a recent algorithmic method, SynRBL. On our CompleteRXN benchmark, the CRB achieves high performance across splits of increasing difficulty, reaching 99.28% equivalence accuracy on the random split and 91.71% on the extreme out-of-distribution split. SynRBL produces many balanced and chemically plausible completions, but with lower accuracy on the benchmark test splits. Across all methods, performance degrades with increasing incompleteness. We observe a substantial drop when evaluating on reactions outside the benchmark (full uncurated USPTO), highlighting the gap between benchmark performance and practical robustness and motivating future work. Data, code and models can be found at: https://github.com/Intelligent-molecular-systems/CompleteRxn-Benchmarking.
Predicting reaction impurities is a critical yet persistently data-limited challenge in pharmaceutical process chemistry. While machine learning models for reaction outcome prediction have advanced rapidly, benchmarking their ability to predict impurities remains impractical due to the absence of curated, publicly accessible datasets. We present OPRD-Imp, a dataset of 229 organic reactions drawn from 62 publications in Organic Process Research & Development, each annotated with experimentally observed impurities and their mechanistic origins. A total of 784 impurity entries is provided, classified into four origin categories. Reactions are represented as reaction SMILES and impurities as individual SMILES strings, with multi-step synthetic route connectivity preserved. All data were manually extracted from the source publications by trained chemists following a standardized extraction protocol, with expert chemical validation and manual structure drawing. OPRD-Imp is intended to serve as a benchmark resource for evaluating models that predict reaction impurities, providing experimentally reported impurity annotations and mechanistic origin labels that are not systematically represented in conventional reaction datasets.
Symmetry governs the organization of physical structures, while symmetry breaking reveals their transformations. In geometric deep learning, symmetry imposes rank constraints on equivariant representations, limiting the expressive capacity of equivariant graph neural networks (GNNs). Here we show that these constraints can instead be exploited: the singular-value spectra of equivariant representations provide a unified fingerprint of structural symmetry. We introduce spectral symmetry fingerprints (SymFP), which enable discrete point-group identification through rank-template matching and continuous symmetry analysis by quantifying spectral energy beyond target rank constraints. SymFP is orientation invariant and architecture agnostic, enabling a parameter-free GNN implementation. Its spectra can be reused across multiple target groups, and the resulting leakage scores satisfy subgroup monotonicity. Across synthetic structures, molecules, coordination complexes and large biological assemblies, SymFP accurately identifies point groups, tracks controlled symmetry breaking and reveals local and degree-resolved symmetry changes that can be obscured by global geometric measures. These results establish the spectral structure of equivariant representations as a general framework for characterizing symmetry across physical systems.
Machine learning approaches are rapidly revolutionizing the ability to analyze and extract structural insights from chemical data, enabling high-throughput chemical discovery. While existing data-driven approaches have shown remarkable promise for predicting chemical structures in the de novo setting, incorporating additional chemically informed context offers the opportunity to further improve these models' performance and extend their real-world utility. Here we provide a straightforward protocol to combine artificial-intelligence-based spectroscopic elucidation pipelines with contextual chemical data, e.g., known reactants or a desired product, by using automated retrosynthetic analysis to generate large training sets of molecules and contextual data in the form of synthetic precursors. We demonstrate our approach by showing that our recently introduced NMR structure elucidation framework can be trained to effectively leverage molecular precursor context. We show that when the chemical context provides useful information on the target molecule we obtain dramatically improved accuracy over using NMR spectra alone, obtaining Top-15 accuracies of up to 95.4% for molecules up to 40 heavy atoms spanning the full elemental range of organic chemistry. Furthermore, we demonstrate that our approach is highly robust, such that even when the context provided is uncorrelated with the target, one still obtains accuracies commensurate with those of the original NMR structure elucidation framework. This approach provides an efficient route to improve a wide range of spectroscopic structure elucidation platforms using contextual data.
Liquid-phase peptide synthesis (LPPS) offers a scalable route to peptide manufacturing, but route development still depends on empirical solvent screens because each protected intermediate must be soluble for reaction and recoverable for purification. The protecting groups, terminal modifications, and noncanonical residues that govern this behaviour are poorly represented in existing peptide property benchmarks, limiting the ability to develop and rigorously evaluate molecular representation models for LPPS-relevant prediction tasks. We introduce PeptSol, an open benchmark of 1388 hand-curated protected-peptide solubility measurements with chemistry-aware splits. The measurements span only 84 parent sequences and 101 protected structures, and 92.5% come from a single historical programme. Across seven frozen molecular encoders, the best macro-F1 is 0.843 on binary solubility for the historical subset under a peptide-held-out split; the harder three-class ordinal task reaches 0.614 in that cell. No foundation model consistently outperforms a baseline combining chemical fingerprints with explicit molecular descriptors, and model rankings vary across prediction tasks and data splits. The dataset, evaluation protocol, and baselines establish a standard for measuring progress on molecular representations for synthesis-aware peptide developability.
Deep eutectic solvents (DESs) offer a tunable platform for lignocellulose refining, but their solvation behavior depends on multicomponent hydrogen-bond networks rather than individual constituent properties. We develop TiNN, a thermodynamics-informed neural network that hierarchically represents HBA-HBD association and solute accommodation through a learned free-energy pathway. Trained on 938 records, TiNN achieves a test-set $R^2$ of 0.917 and generalizes to new HBA-HBD combinations and sparse conditions. Ablation identifies solute-specific stabilization as the largest contributor to prediction accuracy, while the importance of hydrogen-bond compatibility depends on the dissolution mechanism. Experimental measurements of glucose, xylan, and Kraft lignin in acidic, basic, and neutral DESs show that TiNN reduces the geometric mean solubility error from more than 23-fold with COSMO-RS to approximately 1.5-fold. Without training on fractionation data, TiNN also distinguishes DES formulations with high and low lignin and hemicellulose removal from corn stover. These results support chemically grounded solvent screening for lignocellulose fractionation.
Locating competing reaction pathways is difficult when potential-energy gradients are unavailable. Here we present tReax_expedition, an energy-only approach combining coupled Monte Carlo exploration, stochastic quench labelling and restrained continuation. Exploration identifies connected states, while continuation resolves candidate channels and records sampled chain maxima. Single-search benchmarks on three two-dimensional potentials recovered an intermediate and competing routes without transition-state guesses. For eight of nine gas-phase reactions on GFN2-xTB, sampled chain maxima differed from independently refined saddle energies by less than 0.76 kJ/mol. Alanine dipeptide instead revealed incomplete conformational relaxation, showing that route connectivity can persist despite structural and energetic errors. Neural committor learning and local straddling-pair sampling connect the resulting paths to transition-region sampling, although molecular shooting diagnostics indicate limited committor calibration. These results show how energy-only exploration and continuation recover candidate pathways, while distinguishing route connectivity from geometric localization, barrier resolution and finite-temperature transition statistics.
Diffusion models are often inaccurate in critical, data-sparse regions of the target distribution. Sampling from restrained distributions, biased distributions used in classical enhanced sampling to concentrate data near chosen configurations, can control where training data are collected but biases the learned distribution. We establish that this bias cancels exactly when forward noising from restrained data is conditioned on the restrained configuration at an appropriately chosen intermediate time. This allows a pretrained model fine-tuned on restrained data to achieve high accuracy in any chosen region of the target distribution, regardless of its probability, using standard denoising or flow matching objectives without importance weights. When no target data are available, Gibbs sampling enables inference from a model trained exclusively on restrained data.
Metalloprotein docking requires a ligand pose to satisfy both global pocket fit and the identity and geometry of metal-coordinating atoms. General-purpose diffusion docking models do not explicitly condition generation on externally specified complete ligand donor sets, and their predicted poses can exhibit incorrect metal-donor relationships. Metal-aware models address coordination during training and generation; here we ask whether external donor information can correct already-trained general-purpose models without retraining. We propose Complete-Identity Contract Guidance (CICG), which applies a supplied complete donor set through translation, rotation, and torsion updates, and Historical Contract Transfer (HCT), which supplies donor identities from earlier complexes at compatible receptor sites. We compare HCT with trajectory-local controls retaining the historical donor count with or without elemental composition. On 86 assessable HCT-covered queries, HCT-guided CICG increases frozen-confidence-selected joint success from 21.5% to 36.6% on SurfDock and from 25.0% to 34.9% on DiffDock-L. The joint criterion requires correct global ligand placement, complete native donor recovery, coordination geometry, preserved stereochemistry, and absence of fatal receptor clashes. Composition-matched guidance reaches 33.14% and 34.30%, leaving the additional benefit of fixed historical membership unresolved. Our results therefore support donor-set guidance as a conditional correction for frozen docking models, while identifying donor-source reliability and physical-quality preservation as the main barriers to broader use.
Molecular design requires coordinated generation, property prediction and iterative editing, with each decision linked to the correct chemical structure and supporting evidence. Integrating these capabilities in practice presents three major challenges: retaining local control of molecular data, connecting specialized models across tasks and verifying that proposed changes satisfy chemical constraints. Here we present MolCrew, a locally deployable system that coordinates four separately trained molecular specialists with a language-model orchestrator and RDKit calculations. The specialists generate structures from descriptions, describe molecular structures, predict biological endpoints and propose edits towards specified goals. Separate model weights allow each capability to be evaluated and updated independently within the workflow. RDKit calculations check structural validity, quantify descriptor changes and assess specified structural constraints, while returned observations guide further tool calls. We evaluated low-rank adaptation of the orchestrator for tool-use decisions and failure recovery while leaving specialist weights unchanged. On 3,300 ChEBI-20 test examples, MolCrew achieved 96.4% exact structure recovery, compared with 38.7% for published Atomas-large results. Across eight MoleculeNet datasets evaluated using scaffold splits, mean area under the receiver operating characteristic curve was 0.851, compared with 0.770 for published Atomas results. In a recorded evaluation using the unadapted orchestrator, 1,554 of 1,699 requests (91.5%) passed every predefined workflow check. By preserving inspectable links between molecular proposals, model outputs and chemical calculations, MolCrew provides a modular framework for computational candidate assessment and refinement under local data control.
Methyl acetate production via direct carbonylation of dimethyl ether and carbon monoxide involves strong nonlinear interactions among reactor operation, recycle structure, and energy consumption, making conventional simulation-based optimization computationally demanding. In this work, a data-driven framework integrating steady-state process simulation, surrogate modeling, and Bayesian optimization was developed for process intensification. A dataset of 2730 steady-state simulations was generated using a Python-based automated process simulation workflow and a structured design of experiments across the operating domain. Surrogate models were trained to predict carbon conversion yield (C-yield) and cost of specific energy consumption (C-SEC), with neural network-based models showing the best predictive performance and robustness. These models were integrated into a multi-objective Bayesian optimization framework to identify optimal operating regions. Results indicate that high C-yield (up to ~95%) can be achieved with reduced energy cost through lower recycle flow rates and compression demand. Pareto analysis revealed a nonlinear trade-off between C-yield and C-SEC, where further improvements near the conversion limit require disproportionately higher energy input. Validation against rigorous simulations showed deviations below 3% for C-yield and 10% for C-SEC.