Makoto Takamoto, Chaitanya Sampara, Viktor Zaverkin, Daniel Oñoro-Rubio, Mathias Niepert
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.
Heejeong Kim, Seonbin Kim, Jihwan Kim, Tim Pinkhassik, Magdalena Lederbauer, Suong Tran, Connor W. Coley, Juyoung Yoon 等 9 位作者
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.
Jiacheng Cen, Anyi Li, Ning Lin, Zihe Wang, Ji-Rong Wen, Wenbing Huang
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.
Alexander Arjun Lobo, Marc Saouda, Urvi Awasthi, Leonid Zhukov
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.
Frank Hu, Jonathan M. Tubb, Grant M. Rotskoff, Matthew W. Kanan, Thomas E. Markland
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.
Yanpeng Ye, Chaoran Duan, Mian Xu, S. Mani Sarathy
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.
Xuanxi Zhang, Kevin S. Cheng, Weizhou Wang, Aaron R. Dinner, Jonathan Weare
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.
Exchange-correlation functionals are usually fitted with energy-only losses, so better energies often bring worse densities. We introduce a workflow that predicts in closed form, from one Fock build on inverse Kohn-Sham orbitals of any accurate density, a functional's self-consistent density, and fits it to that density with no self-consistent-field solution. Fitted convexly, a CF22D-form hybrid beats CF22D and MN15 on unseen energies, dipole moments, and unfitted densities (6.8- and 22-fold lower density error). A neural meta-GGA fitted to 6 energies and 11 densities beats SCAN in both.
Molecular docking predicts how a small molecule binds to a protein and is a key bottleneck in drug discovery. Classical scoring functions sum empirical pairwise contacts, blind to quantum-mechanical effects like orbital charge transfer that govern binding specificity. We introduce Q-Score, encoding GNN-predicted orbital donor-acceptor energies into a weighted graph and scoring binding by solving a maximum-weight vertex clique problem via Digitized-Counterdiabatic QAOA. Each interaction anchor maps to one qubit and compatibility constraints become edges. Across 11 protein targets, DC-QAOA recovers the exact optimum on 8 at 10 qubits. On 1000 AI-generated molecules, Q-Score is orthogonal to classical scoring with Spearman rho of 0.05, driven by orbital quality with rho of 0.90, and free of molecular-weight bias, enriching for strong orbital interactions at twice the random rate. DC-QAOA achieves a mean approximation ratio of 0.94 with 52 percent exact. Execution of 1000 circuits on IBM Eagle confirms 6-qubit solvability on NISQ hardware.
Foundation machine-learning interatomic potentials (MLIPs) offer one model for many chemistries, but their deep, globally coupled architectures do not fit the spatial decomposition that scales classical and short-ranged MLIPs. We present pair_style uma, a LAMMPS pair style that evaluates the Universal Model for Atoms (UMA) through LibTorch on NVIDIA and Intel GPUs from a single source tree. It reimplements FairChem's edge-sharded graph parallelism in C++ over exported TorchScript modules, with one MPI rank per device, NCCL or oneCCL collectives, and the whole energy and force path in double precision. The strain-gradient virial is carried through the exported modules and the cross-device reductions, so that fix npt runs on both vendors' hardware. We measure NPT capacity and cost on one 4xA100-40GB node, one 8xH200 node, and one 12-tile Intel node, and on up to 32 Intel nodes. Without activation checkpointing, one node holds NaCl cells of about 8,000 atoms (A100, 0.21 ns/day), 22,000 atoms (Intel, 0.10 ns/day), and 47,000 atoms (H200, 0.16 ns/day). Graph parallelism raises the capacity of a single device by 8.0x on H200 and 4.6x on A100. Across nodes, capacity grows to about 779,000 atoms on 32 Intel nodes, with a slower speed at 0.007 ns/day. On H200 and A100, a FLOP count of FairChem's graph-parallel predictor gives lower bounds of 31% and 51% of FP64 peak. From one omat checkpoint and with no refit, nine 100 ps NPT heating ramps (NaCl, equiatomic Pt-Ru, and equiatomic (HfNbTaTiZr)N, on all three node types) ran to completion.
Hamidreza Eivazi, Eslam Sharaawy, Stefan Wittek, André Hebenbrock, Raphael Ginster, Steffen Blömeke
Battery degradation remains a central challenge in the development and broad application of sustainable energy technologies. Accurate degradation prediction is challenging, as battery aging emerges from complex and heterogeneous interactions among cycling behavior, operating conditions, and cell chemistry. Existing machine-learning approaches typically focus on deterministic end-of-life predictions or modeling degradation curves within fixed chemistry settings, leaving probabilistic state of health (SOH) trajectory modeling across heterogeneous chemistries underexplored. We introduce FlowBatt, a use-inspired conditional generative framework that adapts flow matching with a diffusion transformer (DiT) backbone to battery degradation trajectory modeling. FlowBatt models full SOH trajectories as probabilistic degradation processes conditioned on early-cycle capacity data. To strengthen this conditioning pathway, we use explainable AI analysis to diagnose and improve the encoder that maps early-cycle capacity matrices into conditioning vectors. We evaluate FlowBatt on five public benchmark settings spanning diverse chemistries and aging conditions, comparing it with supervised and diffusion-based trajectory models as well as established baselines for remaining useful life (RUL) prediction under shared data splits. FlowBatt achieves the best trajectory-wise SOH prediction performance on all five datasets, with errors below 2.5%, and delivers competitive RUL prediction performance. By generating multiple plausible trajectories, FlowBatt provides empirical prediction intervals for battery degradation modeling. These results indicate that flow-matching-based trajectory modeling is a promising framework for probabilistic battery health prediction.
Remus Teodorescu, Nicolai A. Weinreich, Berke Bilgin, Yi Zhuang, Wenzel Prochazka
An electrochemical-thermal model of the 4680 cylindrical cell is presented: a Doyle-Fuller-Newman model of the electrode stack coupled to a two-node thermal balance of the roll and the can (a thermal DFN, TDFN), solved by an implicit finite-volume scheme. Two cells are parameterised from teardown geometry and open literature, with every value tagged by provenance: the Tesla NMC811/graphite tabless cell and the BYD FC4680 LiFePO4 multi-tab cell. The reaction heat is evaluated at the open-circuit potential of the particle-mean concentration, which restores the heat of mixing. Both sets are calibrated in the same way, with the test fixture identified from the measurement alone. Against the 1C and 2C charge test of Ank et al., the calibrated NMC set follows the mean can temperature within 0.52 and 1.46 K, with a contact heat of 0.94 mOhm matching the authors' estimate for their holder. For the LFP cell, 1C and 2C discharges to 2.0 V were measured on the authors' bench; the fixture conductance (0.337 W/K) follows from the energy balance and the heat capacity (277 J/K) from the cooling. With the end-of-lithiation drop of LiFePO4 restored in the cathode open-circuit potential, the calibrated set follows the can temperature within 0.44 K (1C) and 0.76 K (2C), reproduces the peaks and the relaxation after cut-off. What remains is what a single can node and a single representative particle do not describe: the axial gradient of the NMC can under contact heating, and a gradual decline of the LFP voltage before the knee at 2C, which points to the distribution of particle states in the electrode. The parameter sets (BPX, CSV) and the bench data are openly available.
Hyunwoo Kim, Insoo Park, Ziseok Lee, Wooyeol Lee, Yoorim Gang, Kyungsu Kim
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.
We introduce machine learning models that accurately predict the electron density, the central variable of density functional theory. They are built on Transformer-inspired architectures, which require little computation per parameter and can therefore be enlarged at low cost. The proposed models, SwinUNETR-V2 and its attention-free counterpart NeXtUNETR, achieve state-of-the-art accuracy on QM9, with normalized mean absolute errors in the density averaging 0.075% and 0.046%, respectively. The predicted densities are accurate enough to bypass the self-consistent iteration: a single Kohn-Sham step reproduces the self-consistent electronic structure. For NeXtUNETR, the median errors are 0.036 meV in the total energy, 0.65 meV/angstrom in the forces and 1.8 meV in the HOMO-LUMO gap. The forces not only recover the self-consistent minima in geometry optimization but also successfully drive ab initio molecular dynamics. Fine-tuned on small datasets, both networks also transfer accurately to systems containing elements absent from QM9 or larger than its molecules.
Ishan Amin, Yue Jian, Nitesh Kumar, Christine Zhang, Jianwei Lai, Casey S. Mezerkor, Aaron M. Melemed, Jonathan R. Thurston 等 13 位作者
Accurately predicting the transport properties of liquid electrolytes is critical for next-generation battery design and requires force fields that are both quantum-mechanically accurate and fast enough for long-timescale simulation. Recent large-scale pretrained machine learning interatomic potentials (MLIPs) approach density-functional-theory accuracy, but remain too slow to access the necessary timescales to converge transport properties. We provide a knowledge distillation procedure to transfer the accuracy of a large-scale "teacher" MLIP into fast, system-specific "students", without any additional ab initio data. Our distilled models run ~40x faster, reproduce teacher-predicted structural observables, and produce stable 20 ns trajectories in days, rather than the months the teacher would require. Across a diverse set of sodium- and lithium-ion electrolytes, student-predicted self-diffusivities, ionic conductivities, and shear viscosities track experiment and outperform classical force-field predictions, establishing distillation as a practical route to accurate, long-timescale simulations necessary for high-throughput electrolyte screening.
Juan B. Pérez-Sánchez, Viviana Roman-Ventura, Olalla Nieto-Faza, Aiwei Yin, Alán Aspuru-Guzik, Varinia Bernales
Multireference calculations often require substantial human expertise and time to choose and refine an active space for the electronic states or chemical process of interest. This involves selecting which orbitals to include, verifying that the calculation describes the intended excited state, and deciding whether the results have converged. Here, we ask whether scientific agentic systems (harnesses) can make these decisions reliably. We use the El Agente Quntur multi-agent harness, with GPT-5.6 Sol and GPT-5.6 Terra as the underlying LLM components, to explore 32 diverse singlet excitations at fixed molecular geometries. The agents planned and executed calculations, choosing and refining active spaces under prompts that specified equal-weight two-singlet state-averaged CASSCF followed by strongly contracted NEVPT2 with def2-TZVPD. We evaluate excitation energies against published CASPT2 reference values at matching geometries and compare performance with six deterministic Active Space Finder protocols. Within the El Agente Quntur system, agents detect missing active orbitals, compare candidate excited states, and revise state assignments as calculations progress. Agentic execution reduced mean absolute error by 48\% relative to the state-of-the-art Active Space Finder protocol. We note that computational traces vary substantially across runs in both active space selection strategies and cost, even for the same molecule. Our results underscore the advantage of agentic active space selection over fixed workflows, yet leave room to improve efficiency through runtime-aware decision-making, reduced inter-agent communication overhead and redundancy, more systematic checks of state identity, and clearer stopping criteria.
Fang Sun, Hekai Cheng, Ruoyan Li, Yuanzhou Chen, Wei Wang, Jason Cong, Yizhou Sun
Kohn-Sham density functional theory (DFT) is the standard method for computing the electronic structure of molecules and materials, but its self-consistent-field (SCF) iterations make it expensive for large systems and high-throughput screening. Machine-learned Hamiltonian models offer a shortcut: an equivariant network predicts the Kohn-Sham Hamiltonian matrix in one forward pass, and diagonalizing the prediction yields orbital energies, the HOMO-LUMO gap, molecular orbitals and the electron density. These models are trained to match the reference matrix entry by entry, yet a small entry-wise error does not guarantee accurate eigenvalues or eigenvectors. Two physics-informed alternatives go partway: a recently proposed wavefunction-alignment loss adds a spectral penalty without diagonalizing the prediction, and matching the electron density of the diagonalized prediction supervises it directly. Neither is complete: by representing the prediction error in the eigenbasis of the reference Hamiltonian, we show that each sees only part of the error, and that shifting the predicted orbital energies leaves the electron density exactly unchanged. The same analysis identifies a complete training signal: the cumulative local density of states (cumulative LDOS), the number of electrons at each point in space with energy below a given threshold. The cumulative LDOS is a single physical observable that contains the electron density as a special case, responds to every component of the error, determines the Hamiltonian uniquely, and yields gradients that do not vanish for large orbitalenergy errors. Fine-tuning three Hamiltonian networks on QH9 in this way, which we call FermiScope, reduces the HOMO-LUMO gap error without increasing the element-wise error. The gains carry over to out-of-distribution and molecular-dynamics splits, where the wavefunction-alignment loss helps less.