chemical engineers

Abstract: Theoretical predictions of novel materials rely on a variety of techniques, from data-mining-based ion substitution methods to fully de novo generative models. Each approach imposes specific constraints and encounters unique challenges when extrapolating beyond the distribution of known materials to discover new ones. The foremost goal of materials generation is to produce stable, unique, and novel (S.U.N.) structures. Predicted structures that meet these criteria, however, typically result from novel chemical compositions mapped onto known structural prototypes or frameworks. We leverage this heuristic insight to present a new generative paradigm for the de novo prediction of inorganic crystalline materials constrained by their structural framework---i.e., the unit cell shapes and respective particle positions. Our method, termed OMatG-FC (Open Materials Framework-Conditional Generation), learns via a combination of discrete flow matching on the atomic species and stochastic interpolants for the volume scaling of the unit cell lattice, while fixing in-place the fractional coordinates and the unit-volume lattice vectors, dramatically reducing the dimensionality of the problem compared to unconstrained (framework-free) generation. Our method is more flexible than existing prototype-constrained methods, demonstrating capability for discovery of unseen, stable prototypes derived from known structural frameworks. We also investigate the number of unique frameworks in the MP-20 dataset, demonstrating the propensity of duplicate frameworks within the dataset and providing a framework-split version. We benchmark the performance of our model using the LeMat-GenBench suite using three ML interatomic potentials and achieve state-of-the-art S.U.N. rate below the convex hull, eschewing the need to learn atomic packings for materials discovery.

Abstract: Porous-material adsorption studies require coordinated structure preparation, force-field selection, simulation, validation, and interpretation, making end-to-end automation difficult. We test whether RaspAssistant, a hierarchical multi-agent framework, can carry an adsorption study from force-field preparation through validation and downstream separation analysis. Across twelve multi-agent workflow-reproduction runs spanning four adsorption and separation benchmarks, overall scores ranged from 8.50 to 10.00 on a rubric evaluating workflow correctness, simulation validity, and analysis consistency. In a separate eight-case force-field extraction benchmark, the mean weighted score was 0.967, combining parameter agreement and RASPA readiness. In open-ended studies, the system diagnosed and refined an acetylene force field and, after validating a CO$_2$ force field against MFI experiments, screened 197 pure-silica zeolites that passed automated input checks. These results demonstrate autonomous workflow execution after task specification and input provision: RaspAssistant coordinates, validates, adapts, and documents extended adsorption-simulation workflows while exposing model sensitivity and methodological limitations for expert review.

Abstract: Bayesian optimization (BO) over discrete spaces is challenging due to missing gradients and the sparsity of valid solutions. Latent-space BO sidesteps both issues by fitting a surrogate in the latent space of a generative model, which however substantially complicates the direct incorporation of domain knowledge that is naturally expressed in the original discrete space. In this work, we instead combine a pretrained generative model with a surrogate defined directly in data space, where inductive biases such as domain-specific kernels can be readily incorporated. Rather than maximizing the acquisition function over the discrete design space, our method samples candidates from the generative model under a distribution tilted by the acquisition function. To recover useful gradients for sampling, we embed this tilted distribution into a diffusion bridge that yields a smooth, posterior-averaged acquisition function. This leads to \emph{acquisition function guided generation} (AFGG), which we instantiate with a categorical diffusion model and an autoregressive normalizing flow. Across a broad suite of molecular benchmarks, the diffusion model variant performs on par with leading BO methods, while the flow model variant outperforms state-of-the-art methods in most cases and remains highly competitive otherwise. Our implementation is available at https://anonymous.4open.science/r/afgg.

Abstract: Generating novel molecules with desired properties is a central challenge in drug discovery. Although foundational work focused on de novo generation, practical use cases require a more complex setting: conditioning on an initial seed molecule, optimizing multiple properties, and operating in data-sparse regimes. We introduce PairIT, a flexible training framework for autoregressive transformers over SMILES sequences that enables seeded generation by learning from pairs of structurally similar molecules. By leveraging matched pairs, the model learns to generate local, chemically meaningful edits that improve a property of the seed molecule. Prompt tokens extend this framework by specifying the target property, desired direction, and approximate magnitude of change. Multiple prompt tokens can be concatenated to enable multi-property optimization at inference time. For properties where pair supervision alone is insufficient, reinforcement learning post-training can further improve optimization, providing a tunable trade-off between proximity to the seed and the optimization objective. PairIT naturally supports pretraining on a large dataset and fine-tuning on a smaller dataset, which is critical for performance in data-sparse regimes. Surprisingly, we observe diminishing returns to the scale of the pretraining dataset. We demonstrate empirically on MoleculeNet and Therapeutics Data Commons datasets that, with appropriate paired-data curation, a standard transformer model of modest size (68M parameters) can achieve robust seeded molecular optimization in low-data regimes.

Abstract: Simulation-based Bayesian inference for Chemical Reaction Networks (CRNs) must simultaneously solve two computationally demanding problems: discriminating between overlapping reaction pathways and estimating reaction rate constants. Classical approaches, such as Sequential Monte Carlo ABC, rely on handcrafted summary statistics and scale poorly across large parameter spaces. To overcome this, we introduce a neural inference architecture. Our pipeline utilizes shared 1D-CNNs and a permutation-invariant Set Attention mechanism to learn low-dimensional summary statistics from variable-length, multi-experiment time-series data. These statistics simultaneously condition a model selection network to compute posterior model probabilities and model-specific conditional Invertible Neural Networks (cINNs) that estimate parameter posterior distributions. We demonstrate the practical utility of our approach on a real protodeboronation example, illustrating how it handles structural ambiguity and extracts kinetic parameters from competing catalyst deactivation pathways.

Abstract: Multi-step retrosynthesis planning is often considered solved once a route to purchasable starting materials is found, but such a route should also be practical in real-world chemistry. Recent LLM-based planners formulate this process as sequential decision-making over an AND-OR graph, yet typically expand a single molecule per turn and are optimized for solvability alone, leaving alternative routes uncompared across the multiple objectives that determine practicality before the search budget is committed. We introduce RetroPlanner, an LLM-based planner that jointly compares multiple routes to steer the search toward higher synthesizability, as measured by reaction plausibility, round-trip consistency, and starting-material price. RetroPlanner is trained to reason over chemical evidence: structural progress from the target molecule, bond changes and reaction classes, where candidate routes diverge from one another, and how they rank across multiple objectives. Experiments on multi-step retrosynthesis benchmarks demonstrate that RetroPlanner recovers more alternative routes than prior LLM-based planners while improving synthetic route quality and maintaining a high success rate.

Abstract: Recursive self-improvement (RSI) aims to transform interaction experience into persistent improvements, yet external feedback is costly and world-model predictions may become unreliable as policies evolve. We introduce RSI-Anything, a domain-general framework built on JEPA-Anything that uses predictive world models to guide action and learning-data selection. Observed feedback drives policy or workflow improvement and conditional world-model adaptation, while component and compatibility checks govern the retention of updated policy-model pairs. Across diverse computational and scientific domains, RSI-Anything demonstrates substantial gains. In code repair, with the coder fixed, success increases from 26.3% with a static verifier to 29.2% through predictive selection and 31.2% after world-model adaptation, at comparable test usage. Graphical user interface (GUI) evaluations showed higher task completion, while average actions decrease by 39.4%. Across five successive policy versions, laboratory-planning scores more than double from 21.80% to 46.01%. In reaction optimization, RSI-Anything achieves 96.15% mean best observed yield versus 82.16% for Bayesian optimization under the same 40-experiment budget. An end-to-end immune-science application further connects workflow evolution and predictive modeling with therapeutic hypothesis generation. These results demonstrate how predictive world models and retained system updates enable recursive improvement across diverse environments.

Abstract: Large-scale self-supervised pretraining has reshaped modern machine learning, substantially advancing the ability of language and vision models to generalize across downstream tasks. While deep learning has driven considerable progress in modeling atomistic systems in recent years, self-supervised pretraining in this domain has not yet achieved comparable downstream generalization. To address this, we introduce Atom-JEPA, a self-supervised pretraining framework that learns latent representations from unlabeled 3D structures through complementary atom-level and substructure-level objectives inspired by joint-embedding predictive architectures. We pretrain Atom-JEPA on large-scale molecular and crystalline datasets and evaluate its transfer performance by fine-tuning on a diverse set of downstream property prediction tasks. Atom-JEPA achieves state-of-the-art performance on molecular ADMET and quantum-chemical property prediction tasks, and is highly competitive in predicting the physical properties of crystalline materials. These results demonstrate the potential of latent-space predictive pretraining to support broad downstream generalization from structural data alone. Code and pretrained model checkpoints are publicly available at https://github.com/khelverskovp/atom-jepa

Abstract: Several discrete design tasks, such as molecular discovery, require diverse collections of useful candidates at low computational cost. High validity alone does not guarantee a useful candidate library: repeatedly generating the same valid structures leaves few distinct alternatives. Training for both feasibility and diversity is challenging because many relevant criteria can only be evaluated after hard decoding. To address this challenge, we propose EGO (Evolutionary Generators with One-step inference), a framework for training compact generators directly on discrete outputs. The method combines distribution matching with structural constraints and optional diversity or history-dependent rewards, using antithetic low-rank evolution strategies without requiring criterion-specific differentiable surrogates. Once trained, the generator produces the entire graph in a single neural-network evaluation. On molecular generation benchmarks, our compact generator achieves over $50\times$ the valid-and-unique yield per estimated dense operation compared to recent one-step flow-map baselines while retaining high chemical validity. In scaffold completion, EGO achieves an observed $44.3\times$ speedup over MoLeR in generation to SMILES and produces approximately $10\times$ as many filter-passing proposals within matched time budgets for generation and screening. Beyond chemistry, EGO produces $1.54\times$ as many distinct held-out elite architectures as relaxed gradient training on NAS-Bench-101. The low generation cost may enable real-time candidate generation across discrete design tasks, supporting interactive exploration of constrained design spaces and rapid construction of candidate sets for downstream evaluation.

Abstract: Equivariant machine learning interatomic potentials (MLIPs) have revolutionized atomistic modeling, but accurate treatment of complex materials and molecular systems demands expensive models. This limits simulation length- and time-scales, with tensor products a key computational bottleneck. The recent emergence of foundation-scale MLIPs further exacerbates this challenge. We present Branch Interatomic Potential (BranchIP), a single-model framework for learned adaptive tensor product computation, trained with a novel distillation loss. In our experiments on two systems of physical interest, a heterogeneous catalysis system and a proton-conducting solid acid electrolyte, BranchIP accelerates MLIPs across model sizes by up to $2.4\times$ while reducing memory usage by up to $2.6\times$. This is achieved while maintaining physical fidelity. Furthermore, the learned adaptive computation provides model interpretability by revealing which interactions demand deeper computation and showing how computational depth relates to chemical complexity and dynamics.

Abstract: We introduce Grand Canonical Generators (GCG), a generative framework that extends Boltzmann generators to the grand canonical ensemble. We present two designs. The first conditions a variable-size generative model on the chemical potential, sampling particle number and configuration jointly. The second factorizes the grand canonical distribution into a particle-number distribution and the corresponding canonical Boltzmann density. This factorized formulation can use any existing Boltzmann generator for the canonical component, encodes the known linear chemical-potential dependence analytically, and yields a tractable likelihood that supports self-normalized importance sampling (SNIS). Empirically, GCG accurately reproduces grand canonical observables on a Lennard--Jones fluid and methane adsorption in a zeolite, demonstrating generalization across chemical potentials and correction via SNIS and grand canonical Monte Carlo.

Abstract: Electrolyte formulation design requires balancing multiple physicochemical properties, yet existing models often focus on a limited subset. Learning each property in isolation can overlook transferable chemical information, whereas indiscriminate sharing can introduce cross-property interference. Our directed transfer analysis shows that jointly learning two property prediction tasks can improve or degrade prediction relative to separate training, with asymmetric transfer effects between the tasks. We propose ElectrolyteFM, a unified multi-property prediction model which can more accurately predict multiple properties of each electrolyte by effectively identifying and utilizing property-specific features and knowledge shared across properties. More specifically, ElectrolyteFM learns property-specific representations independently and captures cross-property knowledge through a separately trained expert pool. A router selects relevant shared information for each formulation and target property, and property-specific residual adapters convert this information into corrections to the corresponding representation for prediction. Experiments on Electrolyte12 show that ElectrolyteFM reduces normalized mean absolute error averaged across 12 electrolyte properties by 14.8% relative to the strongest electrolyte-specific baseline. On an independent sodium-electrolyte dataset unseen during training, it reduces conductivity mean absolute error by 6.7% relative to the best-performing baseline.

Abstract: Retrosynthesis enables the discovery of viable synthetic routes to target molecules. It plays a central role in modern drug discovery and materials design. Retrosynthesis involves molecular graph transformations that can change both connectivity and graph size. These transformations may introduce reactant components absent from the target while revising the product-derived structure. To model these transformations, we propose RetroGEF, a flow-based generative model for single-step retrosynthesis. Starting from the target molecule, it constructs possible reactants by adding atoms and changing bonds in the molecular graph. RetroGEF models molecular transformations and changes in graph size within the same generative process, rather than relying on a fixed-size graph canvas. It learns this process directly from product--reactant pairs without requiring a prescribed edit order. Experiments on representative retrosynthesis benchmarks demonstrate that RetroGEF achieves state-of-the-art performance.

Abstract: Deep generative models are widely reported to enable de novo crystal structure prediction (CSP), but their capability has not been measured consistently against template-based methods. We evaluate 12 representative generative CSP models, spanning latent-variable, diffusion, flow-matching, autoregressive, and manifold random-walk architectures, against TCSP 2.0 on 180 test structures and a leakage-controlled subset of 46. All methods use identical structure-matching, symmetry, and consensus criteria. Template retrieval is the strongest single method, reaching 68.3% top-1 success; symmetry-aware EquiCSP (66.4%) and Uni-3DAR (62.9%) form the next tier. However, comparison with TCSP 2.0 shows that most structures correctly predicted by generative models are also correctly predicted by template substitution. Thus, the set of structures uniquely reachable by generation is small, limiting its practical advantage for discovering structures outside existing prototype libraries. To test the source of this performance, we removed entire stoichiometric prototype families from the training set and retrained the strongest generative model. Accuracy declined by 50-78% across four families, establishing that performance is substantially prototype-dependent. A small minority of structures survived removal of their prototype family, demonstrating a real but limited retrieval-independent predictive capacity. Present generative CSP models therefore function largely as implicit, softer-edged prototype libraries rather than genuinely de novo predictors. Enlarging this residual capacity, rather than aggregate match rate alone, is the central open problem.

Abstract: Before a machine learning model can learn a thermodynamic equation of state, it must discover what its measurements represent: which channels scale with system size, which are intensive conjugates, how sectors pair through contact, and which potential governs stability. When sensors expose only an unknown linear mixture of extensive states and intensive responses, passive observations cannot disentangle physical quantities from coordinate artifacts. We formulate the problem of discovering this hidden thermodynamic ontology directly from anonymous controlled experiments. We present an operational identifiability theory and a constructive polynomial-time algorithm that extracts extensive and intensive scaling sectors from replication contrasts, recovers their dual cotangent pairing from thermal contact and reciprocity, verifies a globally admissible concave potential via discrete cyclic concavity, and determines an invariant matroid of reservoir ensembles. We prove that the residual observational equivalence is strictly (x, lambda) ~ (A x, a A^{-T} lambda + beta), establishing the sharp observational limit that no permitted experiment can break. Blind evaluations on van der Waals fluids and Curie-Weiss magnets confirm robust recovery under ill-conditioned mixing, correctly resolving anonymous Maxwell tie-lines while rejecting non-equilibrium continuations. External validation across six real fluids from the NIST WebBook demonstrates that operational ontology discovery transfers across real physical substances without coordinate leakage.

Abstract: Living systems compute with chemistry by mapping environmental signals onto specific internal chemical states. Despite recent advances in molecular programming, it remains unclear which physicochemical features control the computational expressivity of chemical systems. Here we inverse-design thermodynamically consistent chemical reaction networks whose steady-state response to an environmental input computes a target nonlinear function. Using implicit differentiation we train the free-energy landscape directly: standard chemical potentials, transition-state energies and thermodynamic drives. Increasingly large networks generated by elementary ligation and cleavage steps fit increasingly complex nonmonotonic polynomial functions, with expressivity scaling logarithmically with network size, predicted primarily by the number of reactions. Training individual energetic parameter classes reveals that internal thermodynamic drives, capable of breaking detailed balance, dominate trainability, with comparable performances achieved only by pairs of parameter classes. These results identify nonequilibrium drive as the most effective single resource for steady-state computational expressivity in chemical reaction networks.

Abstract: Molecular design is most effective when generation mirrors the edits chemists actually make: extending a scaffold, replacing a substituent, or decorating a scaffold at a specified attachment site while optimizing molecular properties. Fragment-based molecular design naturally supports this workflow, yet existing approaches often separate fragment selection from attachment prediction, first choosing a fragment from a fixed vocabulary and then predicting how it should be connected. This decoupling restricts generation to a closed fragment vocabulary and treats attachment as a separate prediction problem. We introduce Fraglingo, an autoregressive fragment-based molecular generator that jointly models fragment identity and attachment in a continuous latent space. Fraglingo predicts an attachment-aware fragment embedding and retrieves the next fragment through latent-space nearest-neighbor search. To encode attachment context, we introduce a wildcard-anchored readout that represents the growing molecule from the perspective of its active attachment site, enabling the predicted embedding to capture both the molecular context and the required attachment. Because generation operates in a continuous embedding space rather than over fixed fragment identifiers, new fragments can be added to the inference-time vocabulary without retraining, provided their embeddings can be computed by the trained fragment encoder. This retrieval-based formulation provides a unified generation primitive for molecule generation, scaffold generation, scaffold decoration, and molecular optimization. On controlled property-conditional benchmarks, Fraglingo achieves stronger joint property control than comparably trained baselines while maintaining competitive validity, uniqueness, and novelty. Furthermore, Fraglingo generalizes to fragment libraries up to 4x larger than those used during training without retraining.

Abstract: Unraveling reaction mechanisms is central to modern chemistry, yet automating these investigations remains challenging because computational workflows still rely heavily on expert intervention. Here we introduce ARCHE, an autonomous agentic system that integrates a general-purpose reasoning model, a domain-specialized computational chemistry model, and a structured tool registry to transform mechanistic inquiry into a scalable, self-validating process. ARCHE interprets scientific questions, generates and prioritizes mechanistic hypotheses, orchestrates computational workflows, and iteratively refines conclusions based on computed evidence within a closed loop. We validate its capabilities across three increasingly demanding scenarios: reconstructing stereocontrolling transition states and validating the corresponding reaction mechanism in a previously reported asymmetric catalytic reaction; proposing and validating a plausible radical pathway through iterative hypothesis refinement for a recently discovered but unpublished $α$-iodoboronate C-I cleavage reaction; and identifying a chemically interpretable descriptor that governs selectivity in nickel-catalysed migratory cross-coupling reactions. By coupling agentic reasoning with rigorous computational validation, ARCHE advances autonomous mechanistic discovery and establishes a foundation for broader machine-assisted chemical research. The code for ARCHE is publicly available at https://github.com/JetAstra/Arche-Harness.