Molecular Property Prediction

Machine-learned interatomic potentials (MLIPs) excel at in-distribution tasks, accelerating drug and material development, yet they struggle to generalize out-of-distribution. We propose to push the cost-accuracy Pareto frontier by designing observable-agnostic electronic ground-state descriptor models (GSMs) with computational costs situated between MLIPs and Kohn-Sham density functional theory (KS-DFT). We align the learning objectives and architectures of GSMs with the governing equations of KS-DFT by enforcing physical constraints and removing optimization pressure on unphysical or irrelevant degrees of freedom. In our size-extrapolation experiments from QM9 to QM40, our combined contributions OrthoNormal-Loss (ON-Loss) and Grassmann Restricted Occupied-Orbital Training (GROOT) reach a 79.1% energy and 83.4% force mean absolute error (MAE) reduction over previous state-of-the-art density GSMs. For Hamiltonian GSMs, ON-Loss and Residual Optimal-gauge Conditioning-aware KS-Eq. Training (ROCKET) together reduce the energy and force MAEs of the strongest baseline by 99.8% and 95.9%, respectively. Using a self-consistency rejection criterion, we filter out extrapolation errors on QMugs, rejecting fewer than 0.4% of predictions while reaching an energy MAE of 0.07 mHa. Finally, we demonstrate the efficiency of label-free self-consistency fine-tuning, and transfer GSMs to reactive chemistry in Transition1x, reaching energy errors below chemical accuracy.

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

Molecular encoders contrastively pretrained on paired molecule-morphology data, such as CLOOME and CellCLIP, have been proposed as cheap surrogates for phenotypic prediction, avoiding the need to run a Cell Painting assay. We evaluate this idea for these molecular encoders under a protocol designed to control for two confounds that can inflate apparent performance: leakage across an encoder's own pretraining boundary, and the correlation between phenotypic activity and cytotoxicity. Testing six representations, including a non-pretrained MLP control matching CLOOME's input and layer count, on two distinct Cell Painting screens, we find that once these confounds are controlled for, the pretrained molecular encoders show no clear advantage over plain physicochemical descriptors, and that toxicity is generally easier to predict than phenotypic activity across representations. Our results suggest leakage-aware, confound-controlled evaluation should be standard practice before phenotype-pretrained encoders are trusted as surrogates for phenotypic drug discovery.

Existing molecular and materials learning approaches often rely on a limited set of structural representations, which may capture only selected aspects of complex three-dimensional structure. Here, we introduce mathematical invariant-enabled topological neural networks (MITNNs), a framework that represents complex structures through multiple complementary mathematical views and integrates them with topological neural architectures. MITNNs combine multiscale invariants from topology, spectral theory, commutative algebra, differential geometry, and discrete curvature, capturing complementary structural information from the same system. Systematic invariant-subset, architecture-subset, and ensemble analyses show that predictive performance depends on how mathematical representations and neural architectures are paired, with selected combinations outperforming individual models and the aggregation of all available components. Across protein-ligand binding, metal-organic framework properties, mutation-induced protein solubility, and molecular toxicity prediction, MITNN consistently outperforms existing methods. These results establish MITNN as a mathematically multimodal framework for scientific machine learning.

Accurate bioactivity prediction is a central challenge in early-stage drug discovery, as individual assays often contain too few measurements to train reliable models independently. Meta-learning offers a principled approach to this few-shot setting, but assay heterogeneity may limit its effectiveness. Here, we test this hypothesis and show that meta-learning performance degrades as meta-training tasks become more heterogeneous. To address this, we introduce MetaHeta, a meta-learning framework that accounts for assay heterogeneity by conditioning predictions on auxiliary data from related assays, with relatedness defined flexibly from available assay information. The architecture of MetaHeta combines linear attention over large auxiliary datasets with exact attention over scarce task-specific context, enabling efficient scaling to the former without compromising exact attention over the latter. We demonstrate the benefits of our approach on assays from ChEMBL and BindingDB, improving few-shot bioactivity prediction and downstream compound prioritization in retrospective Bayesian optimization.

Every protein has a unique stability landscape, but the physical consequences of mutation are governed by recurring biochemical constraints. We test whether a shared decoder, trained on measurements from diverse proteins, can interpret these constraints in an unseen target, enabling cross-protein transfer for initial experimental round prescreening. We present StabilityArc , which maps frozen ESMC-600M residue representations through a shared RoPE transformer to an Lx20 matrix of substitution effects; a symmetric, contact-aware residual aids in predicting epistasis in simultaneous substitutions. In 66 strict leave-one-protein-out evaluations covering 134,794 ProteinGym variants, StabilityArc achieves 0.7134 Spearman correlation, exceeding the strongest zero-shot baseline, ProSST-2048 (0.6526), by 0.0608. We further explore the utility of this method by providing the score as a prior for Kermut, achieving Spearman correlation of 0.8280 across three supervised split schemes, improving on Kermut's reported 0.8167.

Predicting molecular properties for compounds that differ structurally from labeled training molecules is important for drug discovery and materials design. Tabular foundation models (TFMs) offer a promising approach through in-context learning, but their performance under structural shifts and the value of molecular comparisons in this setting remain underexplored. We study structural generalization in molecular property prediction and introduce MolPAIR (Molecular Pair-Augmented In-context Refinement), a framework that combines molecule-level and molecular-pair contexts without task-specific parameter updates. A global tabular foundation model (TFM) first predicts a query's property from labeled molecular examples. A second frozen TFM predicts differences in prediction errors between the query and labeled reference molecules, using these comparisons to refine the initial prediction. Across 58 MoleculeACE and Polaris tasks, CheMeleon representations combined with TabPFN-3 already outperform each evaluated baseline on a majority of tasks. MOLPAIR further improves this predictor on 46 of 58 tasks, with gains across four molecular representations and three TFM backbones. These results show that explicit molecular comparisons can strengthen tabular in-context learning for structural generalization while keeping the molecular encoder and pretrained model weights fixed. The code and datasets are available at https://github.com/nums-ai/MolPAIR.

Laboratories often face a new molecular assay with 16-64 labels and a bank of predictors whose training data and parameters are unavailable. The practical question is which frozen outputs to include in a small local model. AssayRouter treats completed assays as pseudo-targets and labels each candidate by its post-fit utility: the reduction in held-out discovery loss when the candidate is added to the local target predictor. A shared regressor learns to predict this utility from candidate behavior on the support set, without source identity; on a new assay, one frozen ranking selects four sources and separate labels fit a convex combiner. We train only on completed ChEMBL-MT assays and evaluate 24 external regression assays across six frozen interface families. AssayRouter-C lowers strict four-call negative log-likelihood (NLL) by 0.0409 relative to Support-CV@4. Frozen candidate-label permutations confirm that candidate-utility correspondence carries the transferred information, and leave-one-interface-out training shows that the mapping generalizes to unseen predictor families. Completed assays therefore provide transferable supervision for scarce-label routing through frozen prediction interfaces.

Accurate fitness prediction is central to protein engineering and understanding sequence-function relationships. With advances in deep learning, protein foundation models (PFMs) have become widely used for this task. Recent analyses, however, show that these models share preferences reflecting their training corpora, while unreliable inputs can further distort fitness predictions. Family-specific evolutionary evidence and structural context can help address these limitations by providing complementary constraints on model scores, motivating VenusREM-Harness (VRH), a general, model-agnostic, training-free Retrieval-Enhanced Mutation harness. It fuses frozen model scores with multiple sequence alignment (MSA) evidence according to model uncertainty, then applies gated background correction and score shrinkage based on structural confidence and solvent exposure. Across 1,211 assays and 3.1 million measured variants from ProteinGym, VenusMutHub, and the newly curated viral benchmark VenusViroHub, all 71 configurations improve Spearman correlation on all 3 benchmarks by 0.073 on average, with broad gains across 5 metrics. Extended analyses relate retrieval gains to model-MSA preference differences, assess domain-level gains and immune-escape cases, and quantify computational speedups. Built with VRH, VenusREM2 is the first to rank highest in all function, taxon, MSA-depth, and mutation-depth categories, with a ProteinGym Average Spearman of 0.556, 0.038 above the prior best.

Drug design couples property evaluation, conditional generation, structure-based design, and local optimization, yet machine learning systems typically address these capabilities with separate task-specific models. We introduce CAGenMol-2, a masked diffusion molecular language model that represents molecules, continuous scalar properties, and 3D protein pockets within a single wrapped sequence. Within this pretrained interface, downstream operations are selected by which sequence regions are observed or masked at inference, allowing one checkpoint to perform property prediction, property- and pocket-conditioned generation, and partial-constraint design without task-specific architectures or backbone fine-tuning. We further propose Adaptive Fragment Optimization (AdaFO), a gradient-free mask-and-refill search that turns the masked decoder into an iterative local molecular optimizer. On CrossDocked2020, AdaFO increases Success Rate from 30.2% to 70.8%, the best reported under this protocol, while largely preserving drug-likeness and diversity. Finally, scaffold-preserving directional editing and CRBN/VHL case studies demonstrate its use in compound design workflows spanning local molecular editing, structure-based prioritization, and downstream simulation-based screening.

Molecular property prediction is central to drug development and materials discovery, but experiments are costly and labeled data are scarce. Context-aware methods use auxiliary assay labels to support few-shot prediction, and recent work supervises property relations with label agreement. However, label agreement is sensitive to class marginals and does not directly capture dependence between properties. We propose CalibHyper, a chance-corrected relational hypergraph method based on the joint label distribution. CalibHyper subtracts an independence baseline from the ordered four-state label distribution and shrinks the residual according to the number of joint observations. A swap-equivariant relation head estimates these residuals, which choose the auxiliary properties for each molecule and set the sign and weight of their hyperedge messages. On thirteen datasets from five benchmarks, in both 1-shot and 10-shot settings, CalibHyper and its ablation settings achieve ROC-AUC competitive with the strongest reported results.

Predicting blood-brain barrier (BBB) permeability is critical for central nervous system drug discovery. Using the MoleculeNet BBBP dataset (n = 2039), this study systematically ablates molecular feature spaces to isolate featurisation from model architecture. We evaluate three feature families (Morgan fingerprints, RDKit physicochemical descriptors, SMILES bigrams) across four learning algorithms. Results demonstrate that predictive performance depends jointly on feature representation and algorithm. Dynamic Random Forest using combined features achieved the highest mean AUC (0.970, 95% CI: 0.963-0.977). Second, this optimal representation enables exploratory estimation of heterogeneous associations between molecular structure and BBB permeability using Generalized Random Forests. Constructing a pseudo-treatment from a LogP median split, we applied double/debiased machine learning to account for confounding. Orthogonalization substantially attenuates the heterogeneity detected by naive causal forests; no conditional effects remained significant after false discovery rate correction (smallest adjusted p = 0.082). Furthermore, orthogonalized feature importance shifted toward residual structural information in SMILES bigrams. Ultimately, once observed confounding is properly accounted for, evidence that LogP-BBB associations vary systematically across chemical space is insufficient. This underscores that feature representation and model architecture are coupled design choices, and that unorthogonalized causal forests risk overstating genuine treatment effect heterogeneity.

Vibrational spectral prediction can become inaccurate when localized stereoelectronic environments perturb intermediate response states and high-risk response units dominate characteristic spectral fingerprints, making prediction across external chemical space difficult. SO(3) Equivariant Neural Kalman Networks (SENK) form a response-state cascade that combines an equivariant transformer backbone for Hessian, dipole-derivative and polarizability-derivative learning, an Equivariant Neural Kalman bridge for state-dependent refinement and reliability sensing, and an NBO-informed electronic-prior pathway coupling consistency regularization with bounded, branch-specific guided spectral calibration. SENK outperforms DetaNet on QM9S and QMe14S while preserving full-spectrum IR and Raman fidelity from small molecules to drug-like systems. SENK remains stable and selectively improves spectrally sensitive features in biomolecular systems with complex stereoelectronic effects. It therefore integrates tensor prediction, reliability diagnosis and physics-informed calibration, supporting transferable vibrational spectroscopy from molecular systems to functional molecular materials.

In scientific machine learning, $Δ$-learning trains models on residual errors relative to physical baselines, assuming that more accurate baselines with smaller residual scales inherently improve downstream performance. Here, we demonstrate that residual scale alone is an insufficient heuristic for learnability. Evaluating molecular graph neural networks on total energy targets, we show that complex local descriptor baselines can yield small residual targets that are disproportionately rough within architecture-informed proxy spaces and harder to learn relative to their scale. Conversely, semi-empirical baseline reduces both scale and normalized roughness, improving in-domain and out-of-domain prediction. We introduce scale-normalized graph Dirichlet roughness ($D_{\text{IQR}}$) as a pre-training diagnostic for residual learnability and establish baseline complementarity as a core target-design principle, elevating target space formulation alongside model architecture as a key axis for scientific machine learning.

Drug toxicity prediction is critical for reducing late-stage attrition in drug discovery, yet remains challenging due to severe class imbalance, scaffold-based generalization, and the clinical need for interpretable predictions. Single-modality approaches-SMILES Transformers or graph neural networks capture complementary aspects of molecular structure, while sequence-only models cannot directly provide graph-attributed explanations. We present SMILESGNN, a multimodal architecture that fuses a SMILES Transformer encoder and a GATv2 graph encoder via cross-attention, and SMILESGNN-PT, a variant using a ChemBERTa-2 pretrained backbone. The design retains an explicit graph branch within the predictive pipeline, supporting GNNExplainer-based analysis of substructures associated with toxic predictions. On ClinTox, SMILESGNN achieves AUC-ROC 0.987 and F1 0.906 with only 0.4M parameters, performing competitively with a strong SMILESTransformer and a larger ChemBERTa-2/GATv2 concat-fusion baseline. On Tox21 (12 tasks), SMILESGNN-PT obtains mean AUC-ROC 0.750, comparable to ChemBERTa-2 alone and the same-backbone concat-fusion baseline. Overall, the results suggest that cross-attention is a practical fusion alternative that preserves competitive predictive performance while enabling graph-based interpretability support.

Intrinsically disordered proteins (IDPs) differ from folded proteins in that they are dynamic, lack a stable three-dimensional conformation, and have low sequence similarity between similar proteins. The conformational heterogeneity of IDPs - while beneficial for their diverse functions - limits the use of traditional experimental tools to determine their conformation. The experimental difficulty, along with low sequence similarity, results in data scarcity, and makes it difficult to classify/detect IDPs that are similar or dissimilar, a task relevant to understand biology and evolution. We address this challenge using Multi-task ProtBERT (MT-ProtBERT), a multi-task extension of ProtBERT tailored for low-data regimes. MT-ProtBERT integrates Dynamic Window Masking, a Multi-Scale 1D Convolutional classifier (MS-Conv1D), and auxiliary objectives that jointly optimize masked language modeling and biochemistry-informed tasks. We evaluate this framework on two tasks under limited data: (i) phosphorylation site prediction (S/T/Y) in short sequences and small datasets, and (ii) protein compaction prediction on two small datasets (684 and 530 sequences), including sequences comparable in length to typical disordered regions. MT-ProtBERT consistently outperforms PARROT, an RNN-based IDP-specific model, across all tasks. These results demonstrate that combining self-supervised and biochemistry-informed tasks, and multi-scale learning enables robust modeling of unstructured proteins under data scarcity.

Molecular property prediction is often limited by the small size of labeled downstream datasets, motivating pretraining on large corpora of unlabeled molecules. In this work, we ask whether useful inductive biases can instead be learned from abstract, procedurally generated data before a model sees any molecular data. We introduce a three-stage training pipeline consisting of procedural pretraining, molecular pretraining on SMILES, and downstream fine-tuning, and evaluate several procedural tasks spanning sequence structure, cellular automata, and graph reasoning. We find that procedural pretraining can improve molecular property prediction even after subsequent molecular pretraining: on Lipophilicity, \textsc{Reverse} reduces test error by 4.8%. For context, the magnitude of this improvement is roughly 90% of the performance difference between our 250K-molecule baseline and the publicly released MoLFormer checkpoint pretrained on approximately 100M molecules. Our analysis shows that the benefit is strongest under downstream data scarcity, depends on the structure of the procedural data rather than only surface-level statistics, and does not increase monotonically with additional procedural training. Instead, transfer typically peaks at an intermediate procedural budget and deteriorates as the model approaches convergence on the procedural task. We further find that, for several tasks, much of the transferable information is localized in the attention layers, while feed-forward layers can contribute to over-specialization. These results show that procedural data can provide transferable structure for molecular learning and offer a complementary route to improving performance when labeled molecular data are limited.

Molecular property prediction requires representations that generalize from limited labeled data to structurally novel compounds. Existing molecular pretraining methods often rely on a single view: graph-based approaches model atom-bond topology but provide limited fragment-level supervision, whereas fingerprint descriptors encode chemical patterns but are typically used as fixed auxiliary features. We propose HiFi-Mol, a multi-view framework that separately pretrains a hierarchical graph encoder and a contextualized fingerprint encoder before downstream integration. The graph branch uses fragment-aware masking with multi-resolution supervision to capture substructure-aware representations, while the fingerprint branch tokenizes active entries from seven fingerprint families and applies masked language modeling to learn contextualized embeddings. During fine-tuning, HiFi-Mol combines projected multi-resolution graph features with fingerprint embeddings for downstream prediction. Evaluated on MoleculeNet benchmarks under the scaffold split, HiFi-Mol achieves a 2.77% improvement in average ROC-AUC over the best baseline across eight classification tasks while maintaining competitive performance on three regression tasks. Further analyses reveal that fragment-aware masking improves graph representation quality, and classification results demonstrate dataset-dependent strengths of the individual graph and fingerprint variants, confirming that the two views provide complementary predictive signals.

Collision cross section (CCS), derived from ion mobility mass spectrometry, is a common descriptor for molecular annotation. Prediction is challenging for machine learning models because it reflects the size, shape, and ionization state of a gas-phase molecular ion. Most predictors either ignore explicit 3D structure or treat adduct identity as a late categorical feature, which limits their ability to capture adduct-dependent geometric effects. We present GRACE (Geometric Residual Adduct Conditioning via Early-fusion), a 3D CCS predictor that adapts a pretrained molecular geometry encoder using geometric residual adduct conditioning via early fusion. GRACE combines two inductive biases: a residual objective relative to an adduct-aware physical descriptor baseline and adduct conditioning within the encoder via a learned adduct token and low-rank attention adapters. We evaluate the model on a curated set of over 9,000 experimental molecule-adduct CCS records with random, scaffold, and adduct-sensitive splits designed to separate interpolation, scaffold generalization, and adduct-driven generalization. GRACE achieves the best mean percentage difference among the evaluated learned models on all three splits: 1.67% on the random split, 2.11% on the scaffold split, and 2.36% on the adduct-sensitive split. Diagnostic analyses suggest that residual learning stabilizes training by removing the dominant mass-CCS trend, while early fusion improves adduct-sensitive prediction relative to late fusion. Across four independent external test sets, GRACE shows consistently lower error than the other evaluated models. On a held-out set, GRACE also attains the lowest mean percent difference when compared with four previously reported physics-based workflows. These results support residual learning and encoder-level adduct conditioning as practical inductive biases for fast, accurate CCS prediction.

Enantiomers share atoms, bonds, and pairwise distances yet can behave differently in chiral environments, so molecular encoders must respect atom relabelings and proper rotations without becoming blind to reflection. We introduce GSF-$\chi$, a graph transformer in which stereogenic units modulate all pairwise interactions rather than single out one atom as special. Each central or axial stereogenic unit creates a reflection-even phase field over all atoms, a handedness pseudoscalar $\chi$ sets the direction of a relative rotation on latent query--key blocks, giving a \textbf{Chiral-RoPE} that reflection inverts rather than leaves fixed. A $C_2$ projection separates mirror-even ECD peak counts and positions from mirror-odd peak signs. We prove the operator's even--odd decomposition and its annotation-inversion, permutation, and unit-order identities under explicit canonical-role conditions; property tests and a coordinate-reflection audit verify the laws end to end. GSF-$\chi$ leads every central-ECD output and improves axial Rotation and Symbol by $12.6\%$ and $7.9\%$ over the strongest baseline. Equal-budget controls attribute the Rotation advantage to global signed support rather than parameter or edge count; the $C_2$ projection yields exact enantiomer-pair consistency at a small raw-accuracy cost under complete supervision and becomes predictive when mirror supervision is scarce.

Machine olfaction trains on pooled public descriptor corpora, but whether a shared descriptor word measures the same thing across corpora has not been tested, nor has the ceiling of what any of them can measure. We audit four corpora from Pyrfume. Conditioning on the molecule makes McNemar's test the exact conditional test of the corpus effect. Corpora disagree heterogeneously across descriptors ($I^2 = 80\%$) and non-uniformly with labelling breadth ($z = 17.2$), so no single offset repairs pooling. Median tetrachoric agreement is 0.795 against median $\kappa$ of 0.413: sources largely concur on which molecules deserve a word and differ on how readily they apply it. Of 109 descriptors with an estimable effect, 36 show large differential functioning on the ETS scale. Against a human panel's reliability, Morgan fingerprints with the full RDKit descriptor block reach 32.9% of achievable; adding every label from two merged corpora reaches 33.9%. The gap does not close with model capacity, encoding choice, more molecules, or more words. The missing variance is valence. One pleasantness rating per molecule reaches 54.6% of achievable (57.1% on an independent older instrument). Valence recovered from descriptors ($\rho = 0.457$) yields only 16.6%, so it must be measured. Five raters exceed structure plus the full descriptor record; fifteen to twenty saturate. We release a descriptor crosswalk and twenty machine-checked theorems.

Quantum reservoir computing (QRC) uses quantum dynamics to represent input histories for prediction through a trained classical readout. Discrete time crystals (DTCs) exhibit robust subharmonic responses under periodic driving, and previous work has used their dynamics to construct DTC-QRC. Here we construct a DTC-based reservoir architecture to predict molecular properties from structural and dynamical observations. Coherent Floquet evolution processes local molecular graph events and surface-hopping frames, while controlled reset regulates the contribution of earlier inputs. Measurements at the end of each input sequence yield a feature vector of fixed dimension. Trained classical decoders use this vector for inhibitor-activity and blood--brain-barrier permeability classification and electronic-gap forecasting, while the reservoir parameters remain fixed during training. With matched input lengths and output widths, DTC-QRC outperforms echo-state networks on long-prefix graph classification and the studied ethene gap forecasting tasks. Dephasing lowers performance in both applications, consistent with a role for coherent propagation. Experiments on the Quafu superconducting quantum cloud platform show that pair observables retain task information under device noise. The architecture provides a common framework for molecular screening and time-resolved property prediction using quantum reservoir computing.

Blood-brain barrier (BBB) permeability is a critical determinant in the development of central nervous system therapeutics because it directly influences the ability of drug candidates to reach their target sites within the brain. In this study, an explainable machine learning framework was developed to predict BBB permeability using molecular descriptors generated from the MoleculeNet BBBP dataset with the RDKit cheminformatics toolkit. Fifteen physicochemical descriptors extracted from 2,039 compounds were used to train four supervised machine learning algorithms, including Logistic Regression, Support Vector Machine (SVM), Random Forest, and Extreme Gradient Boosting (XGBoost). Hyperparameter optimization was performed using GridSearchCV, while model interpretability was investigated using SHapley Additive exPlanations (SHAP). Among the evaluated models, the optimized XGBoost classifier achieved the best predictive performance, with an accuracy of 88.97%, a precision of 88.92%, a recall of 97.76%, an F1-score of 93.13%, and a ROC-AUC of 0.9282. Stratified five-fold cross-validation further demonstrated the robustness of the proposed model, yielding a mean ROC-AUC of 0.8982 +/- 0.0130. Feature importance and SHAP analyses consistently identified TPSA, HBD, and LogP as the most influential molecular descriptors governing BBB permeability prediction. Overall, the proposed framework provides an accurate, interpretable, and computationally efficient approach for BBB permeability prediction and may serve as a valuable tool for the early-stage screening of CNS drug candidates.

Proteins perform diverse cellular functions, and even single amino-acid substitutions can alter stability, activity, or molecular interactions. Protein language models (PLMs) provide a scalable approach for modeling such sequence--function relationships from unlabeled sequences, but increasing the size of dense Transformer backbones often brings substantial computational cost without consistently improving mutation-sensitive prediction. We introduce ProtLingo, an efficient PLM framework that augments a pretrained single-sequence backbone with conditional local memory and sparse expert routing. ProtLingo maps contextual residue representations into route-specific discrete codes, composes centered local windows into latent $N$-gram addresses, and retrieves reusable residual signals associated with recurring local sequence contexts. In parallel, selected feed-forward blocks are upcycled into sparse Mixture-of-Experts layers with shared and routed experts, enabling residue-dependent computation while activating only a subset of parameters. Experiments on protein fitness prediction, FLIP benchmarks, and supervised contact prediction show that ProtLingo achieves competitive performance with a 150M-scale backbone, including strong parameter efficiency on mutation-effect prediction and preserved long-range structural representations.

Large language models (LLMs) are increasingly employed to predict molecular properties. However, prediction error alone cannot distinguish prediction from retrieval of published values. We audit 22 frontier models on 12 molecular regression datasets in a zero-shot setting, assessed against a molecule-blind reference derived from each dataset's labels. Significant retrieval is concentrated on 5 datasets, with isolated flagged LLMs elsewhere. Increasing the reasoning setting raises the number of flagged model--dataset combinations from 47 to 89 of 264. An in-context blinding experiment reduces retrieval but leaves a quarter of the combinations flagged. Blinding changes model rankings and increases errors. Because blinding also removes chemically interpretable structure, the error increase can only be partially attributed to reduced retrieval.

Clinical trials in the UK can cost up to £1.3 million, with approximately 90% drug failure rate. Toxicity is a major contributing factor in drug failure. Testing is time and cost intensive. In recent years, the use of artificial intelligence has been increasingly explored to aid in the prediction of drug toxicity, with extensive use of large language models (LLMs). However, LLMs can show considerable variation when minor changes are made to prompts, which raises concerns about their sensitivity to prompt engineering. Prompt engineering is used to optimise a prompt given to an LLM to generate the desired output. This paper proposes a method to analyse prompt engineering for drug toxicity prediction. The aim of the paper is to investigate the importance of prompt phrasing for drug toxicity prediction. LLMs were prompted to identify chemical properties of significance when predicting drug toxicity. Prompts were constructed to investigate; job role, prompt structuring, and rule interpretation. LLMs were then used to generate datasets, using the identified features from initial prompting, which were then passed to machine learning algorithms. The experiments show that the natural variance which occurs in LLMs outweighs any fine-tuning of prompts. There were, however, substantial improvements in model performance when using chemoinformatic code to extract features instead of using LLM-generated values. The proposed analysis methodology is applicable to a wide range of prompt types across different areas of bioinformatics.

Activity-cliff ranking remains difficult because local structural changes can cause large activity differences, while high-quality data that resolve the underlying mechanisms remain limited. To use available activity labels more effectively, we combine absolute-activity regression with ranking-consistency learning. CliffRank trains two parallel predictors with mean squared error, a thresholded listwise loss, and Pairwise Preference Consistency (PPC), which aligns relative ordering in the preference-probability space. On three antimicrobial peptide datasets, CliffRank with ESM2-t12 achieved the highest mean Spearman correlation of 0.5393 and mean Recall@50 of 21.4, although the leading method varied across individual datasets. On three small-molecule datasets, CliffRank with PNA, where PPC was activated after 120 epochs, achieved the highest mean Spearman correlation of 0.6890, while its mean Recall@50 of 30.4 matched that of ACANet-PNA. The PPC results also define its practical limits. Asymmetric initialization improved the MolCLR-GIN averages but did not improve every target. For PNA without pretrained weights, delayed PPC improved selected metrics, but no schedule was best for both mean Spearman correlation and mean Recall@50. Future work should evaluate more targets and antimicrobial peptide systems, develop adaptive PPC schedules, and incorporate protein or membrane context when available.

Accurate molecular property prediction requires both statistical reliability and chemical reasoning. Graph neural networks can be calibrated directly on labeled assays but remain limited by the coverage of their training data. Large language models (LLMs) can compare molecular evidence and articulate chemical rationales, yet are unreliable as standalone quantitative predictors. The central challenge is therefore to determine when an LLM should influence a calibrated model and by how much. Here we present CoMPASS, a retrieval-calibrated framework for small-large model collaboration. CoMPASS retains a graph attention network (GAT) as the predictive anchor, retrieves locally relevant training molecules, provides attention-grounded evidence to an LLM, and converts its proposal into a bounded correction through an agreement-aware gate. Across six classification and two regression benchmarks, CoMPASS improves the GAT anchor in regions of correctable uncertainty while limiting LLM intervention in high-confidence regimes. Ablations show that the gains arise from validation-calibrated retrieval and bounded fusion rather than prompting alone. These results suggest that generative reasoning should augment calibrated prediction through evidence-grounded, controlled corrections rather than direct output replacement. Code is available at https://github.com/littlepeachs/CoMPASS.

Optimizing absorption, distribution, metabolism, and excretion (ADME) is an important part of small molecule drug discovery. Many machine learning models have been built to predict ADME properties to facilitate this optimization process, but explaining model predictions is challenging. We propose a new graph neural network architecture with built-in meaningful per-atom attributions. Our model MolLedger outputs predictions that are the sum of per-atom scores. MolLedger's additive framework obtains exact interpretability at no cost to performance because the global context vector gives the additive head enough context to produce good per-atom scores. Furthermore, MolLedger produces attributions that are more faithful to chemical properties than other interpretability methods because the auxiliary loss in MolLedger anchors the atom scores to chemical properties. Our case studies comparing interpretations from multiple methods on molecular pairs reveal that MolLedger is much better at producing sensible explanations for predicted property changes.

Molecular toxicity prediction is increasingly used to prioritise compounds before experimental testing, but conventional benchmark performance can overstate practical utility when structurally related molecules occur across training and test folds. We introduce ToxLens, a reproducible multi-task graph-learning framework for 11 toxicity endpoints spanning Ames mutagenicity, acute oral toxicity, hERG inhibition, and Tox21 nuclear-receptor and stress-response assays. The workflow combines conservative chemical curation, sphere-exclusion filtering, a leakage-aware UMAP-HDBSCAN split, parallel graph and global-feature encoders joined by late concatenation, temperature-scaled Monte Carlo dropout with conformal-style prediction sets, applicability-domain analysis, and SHAP-guided toxicophore discovery with occlusion controls. On the leakage-controlled test fold, a five-seed soft-voting ensemble achieved a Matthews correlation coefficient score of 0.44, an area under the receiver operating characteristic curve score of 0.83, and an area under the precision-recall curve score of 0.58. It exceeded four ECFP4-based shallow baselines on all 11 endpoints under the same split and validation-based threshold-selection protocol. Controlled ablations showed that the global pathway was important, whereas late concatenation outperformed the tested gated and feature-wise linear modulation fusion variants. Conformal-style prediction sets revealed substantial endpoint-specific variation in set efficiency, and discrimination and calibration improved with similarity to the training domain. Retraining on fixed published Tox21 Challenge and TDA folds produced competitive, but not uniformly state-of-the-art, performance. SHAP-guided occlusion and consensus subgraph mining yielded model-derived structural hypotheses, 44 of which contained at least one occurrence that passed the predefined counterfactual criteria.