Daily Papers

We propose EMBER, a structure-based framework for TCR--pMHC binding prediction that eliminates the need for a predicted docked complex, and with it the placement error that dominates such predictions. Traditional structure-based predictors utilize the co-folded complex structure of the receptor and the antigen and interpret binding from its contact surface. Consequently, every downstream feature inherits any deviation the structure-prediction tool introduced. Methodologically, EMBER folds the TCR and pMHC independently, encodes them as SE(3)-invariant residue graphs, and compares their learned representations without constructing a shared coordinate frame. A relative pose is therefore not an input of the model, so placement error cannot propagate into the prediction. Computationally, EMBER preprocesses O(N{+}M) monomer folds where a complex-based predictor needs O(NM) operations. Experimentally, under epitope-disjoint evaluation with six retrained baselines, EMBER is first on every metric under all four folding tools, by 0.9 to 14.4% in micro-AUROC, 18.5 to 25.3% in micro-AUPRC and 10.6 to 24.1% in MCC. Its ranking is also up to 85% more stable across folding tools.

Understanding cellular machinery requires atomic-scale reconstruction of large biomolecular assemblies. However, predicting the structures of these systems has been constrained by hardware memory requirements of models like AlphaFold 3, imposing a practical ceiling of a few thousand residues that can be processed on a single GPU. Here we present NVIDIA BioNeMo Fold-CP, a context parallelism framework that overcomes this barrier by distributing the inference and training pipelines of co-folding models across multiple GPUs. We use the Boltz models as open source reference architectures and implement custom multidimensional primitives that efficiently parallelize both the dense triangular updates and the irregular, data-dependent pattern of window-batched local attention. Our approach achieves efficient memory scaling; for an N-token input distributed across P GPUs, per-device memory scales as O(N^2/P), enabling the structure prediction of assemblies exceeding 30,000 residues on 64 NVIDIA B300 GPUs. We demonstrate the scientific utility of this approach through successful developer use cases: Fold-CP enabled the scoring of over 90% of Comprehensive Resource of Mammalian protein complexes (CORUM) database, as well as folding of disease-relevant PI4KA lipid kinase complex bound to an intrinsically disordered region without cropping. By providing a scalable pathway for modeling massive systems with full global context, Fold-CP represents a significant step toward the realization of a virtual cell.

Recently, significant progress has been made in protein-ligand docking, especially in modern deep learning methods, and some benchmarks were proposed, e.g., PoseBench, Plinder. However, these benchmarks suffer from less practical evaluation setups (e.g., blind docking, self docking), or heavy framework that involves training, raising challenges to assess docking methods efficiently. To fill this gap, we proposed PoseX, an open-source benchmark focusing on self-docking and cross-docking, to evaluate the algorithmic advances practically and comprehensively. Specifically, first, we curate a new evaluation dataset with 718 entries for self docking and 1,312 for cross docking; second, we incorporate 22 docking methods across three methodological categories, including (1) traditional physics-based methods (e.g., Schr\"odinger Glide), (2) AI docking methods (e.g., DiffDock), (3) AI co-folding methods (e.g., AlphaFold3); third, we design a relaxation method as post-processing to minimize conformation energy and refine binding pose; fourth, we released a leaderboard to rank submitted models in real time. We draw some key insights via extensive experiments: (1) AI-based approaches have already surpassed traditional physics-based approaches in overall docking accuracy (RMSD). The longstanding generalization issues that have plagued AI molecular docking have been significantly alleviated in the latest models. (2) The stereochemical deficiencies of AI-based approaches can be greatly alleviated with post-processing relaxation. Combining AI docking methods with the enhanced relaxation method achieves the best performance to date. (3) AI co-folding methods commonly face ligand chirality issues, which cannot be resolved by relaxation. The code, curated dataset and leaderboard are released at https://github.com/CataAI/PoseX.

A hallmark of neurodegenerative diseases such as Alzheimer's and Parkinson's is the aberrant aggregation of proteins into amyloid fibrils, and small molecules that selectively bind to these fibrils hold promise as diagnostics, imaging probes, and therapeutics. Predicting how such ligands bind to fibril targets, however, presents two fundamental challenges. First, resolved co-crystal structures of amyloid-ligand complexes are exceptionally scarce; even with recent advances in cryo-EM only a handful have been structurally characterized, making supervised training of docking models impractical for this target class. Second, amyloid fibrils present a binding mode fundamentally different from globular proteins: ligands intercalate into longitudinal cross-β grooves and stack cooperatively along the fibril axis, a geometry that existing docking models are not designed to capture. To address these challenges, we present CORAL (COopeRative Amyloid Ligand docking), a reinforcement learning framework that trains a generative docking model to produce ligand pose distributions tailored to the cross-β groove geometry. Our reward explicitly incorporates cooperative ligand-ligand stacking energy alongside protein-ligand docking affinity, directly capturing the distinctive binding geometry of amyloid fibrils. We further introduce a curated evaluation set of amyloid-ligand complexes constructed from model-generated poses validated by domain experts. Experiments on both experimentally resolved structures and this evaluation set demonstrate improved pose quality and binding affinity correlation over existing docking baselines.

Accurately modeling biomolecular interactions is a central bottleneck in biology and therapeutic discovery. Here, we introduce Open Drug Discovery Engine (OpenDDE), an open-source, all-atom biomolecular foundation model that uses co-folding as the entry point to a scalable AI-driven drug discovery engine. Rather than treating structure prediction as an isolated endpoint, OpenDDE is designed as a shared structural reasoning layer for modeling sequence-structure-function relationships across biomolecular complexes, enabling complex structure prediction today while providing a foundation for de novo design, affinity estimation, structure-conditioned optimization, and more. OpenDDE integrates advances in all-atom architecture, atomic latent reasoning, inference optimization, and large-scale data processing to achieve IsoDDE-level co-folding accuracy within a reproducible and openly accessible framework. We also identify two scaling-law directions for co-folding models, revealing practical routes for continued improvement through data, model, inference, and training scaling. By releasing training code, inference pipelines, checkpoints, and benchmarks, OpenDDE aims to democratize access to frontier biomolecular intelligence, accelerate global collaboration, and lay an open foundation for next-generation drug discovery systems that can move from predicting molecular structures toward designing, scoring, and optimizing therapeutic candidates for human health.

Accurately predicting the three-dimensional structures of protein-ligand complexes remains a fundamental challenge in computational drug discovery that limits the pace and success of therapeutic design. Deep learning methods have recently shown strong potential as structural prediction tools, achieving promising accuracy across diverse biomolecular systems. However, their performance and utility are constrained by scarce experimental data, inefficient architectures, physically invalid poses, and the limited ability to exploit auxiliary information available at inference. To address these issues, we introduce Pearl (Placing Every Atom in the Right Location), a foundation model for protein-ligand cofolding at scale. Pearl addresses these challenges with three key innovations: (1) training recipes that include large-scale synthetic data to overcome data scarcity; (2) architectures that incorporate an SO(3)-equivariant diffusion module to inherently respect 3D rotational symmetries, improving generalization and sample efficiency, and (3) controllable inference, including a generalized multi-chain templating system supporting both protein and non-polymeric components as well as dual unconditional/conditional modes. Pearl establishes a new state-of-the-art performance in protein-ligand cofolding. On the key metric of generating accurate (RMSD < 2 Å) and physically valid poses, Pearl surpasses AlphaFold 3 and other open source baselines on the public Runs N' Poses and PoseBusters benchmarks, delivering 14.5% and 14.2% improvements, respectively, over the next best model. In the pocket-conditional cofolding regime, Pearl delivers 3.6times improvement on a proprietary set of challenging, real-world drug targets at the more rigorous RMSD < 1 Å threshold. Finally, we demonstrate that model performance correlates directly with synthetic dataset size used in training.

Identifying protein-ligand binding sites (pockets) is important for understanding protein function and developing drugs. However, no public method has leveraged co-folding models for novel pocket prediction; furthermore, this task lacks a suitable benchmark as existing benchmarks are within the training distribution of co-folding models. We therefore developed PocketWatch,a curated dataset of biologically relevant ligand pockets. The PocketWatch test set consists of unseen pockets stratified by sequence similarity, structural similarity, and crypticity to enable evaluation of generalization to novel and challenging pockets. Using this dataset, we develop zPocket, a method that trains pocket-prediction heads on top of frozen features from co-folding models. We show that zPocket heads outperform baseline methods across all stratifications. Our best zPocket model achieves overall per-target AUPRC of 0.745 compared to 0.598 and 0.595 for the strongest baselines, VN-EGNN and UniSite-1D retrained on the PocketWatch split (0.559 and 0.531 when using the published weights); the widely used P2Rank reaches 0.477. We further show that zPocket can be used to outperform baseline methods on top-N+2 recall of predicted pocket centroids through clustering per-residue predictions or using zPocket to rescore centroids proposed by other models. Finally, we explore two applications of zPocket: crystallographic fragment screens and a proteome-scale scan for uncharacterized pockets on human proteins. Together these results suggest that zPocket heads built on co-folding trunk features can greatly advance ligand binding site prediction.

The effects of ligand binding on protein structures and their in vivo functions carry numerous implications for modern biomedical research and biotechnology development efforts such as drug discovery. Although several deep learning (DL) methods and benchmarks designed for protein-ligand docking have recently been introduced, to date no prior works have systematically studied the behavior of the latest docking and structure prediction methods within the broadly applicable context of (1) using predicted (apo) protein structures for docking (e.g., for applicability to new proteins); (2) binding multiple (cofactor) ligands concurrently to a given target protein (e.g., for enzyme design); and (3) having no prior knowledge of binding pockets (e.g., for generalization to unknown pockets). To enable a deeper understanding of docking methods' real-world utility, we introduce PoseBench, the first comprehensive benchmark for broadly applicable protein-ligand docking. PoseBench enables researchers to rigorously and systematically evaluate DL methods for apo-to-holo protein-ligand docking and protein-ligand structure prediction using both primary ligand and multi-ligand benchmark datasets, the latter of which we introduce for the first time to the DL community. Empirically, using PoseBench, we find that (1) DL co-folding methods generally outperform comparable conventional and DL docking baselines, yet popular methods such as AlphaFold 3 are still challenged by prediction targets with novel protein sequences; (2) certain DL co-folding methods are highly sensitive to their input multiple sequence alignments, while others are not; and (3) DL methods struggle to strike a balance between structural accuracy and chemical specificity when predicting novel or multi-ligand protein targets. Code, data, tutorials, and benchmark results are available at https://github.com/BioinfoMachineLearning/PoseBench.

Protein folding is the intricate process by which a linear sequence of amino acids self-assembles into a unique three-dimensional structure. Protein folding kinetics is the study of pathways and time-dependent mechanisms a protein undergoes when it folds. Understanding protein kinetics is essential as a protein needs to fold correctly for it to perform its biological functions optimally, and a misfolded protein can sometimes be contorted into shapes that are not ideal for a cellular environment giving rise to many degenerative, neuro-degenerative disorders and amyloid diseases. Monitoring at-risk individuals and detecting protein discrepancies in a protein's folding kinetics at the early stages could majorly result in public health benefits, as preventive measures can be taken. This research proposes an efficient pipeline for predicting protein folding kinetics with high accuracy and low memory footprint. The deployed machine learning (ML) model outperformed the state-of-the-art ML models by 4.8% in terms of accuracy while consuming 327x lesser memory and being 7.3% faster.

Protein interaction modeling is central to protein design, which has been transformed by machine learning with applications in drug discovery and beyond. In this landscape, structure-based de novo binder design is cast as either conditional generative modeling or sequence optimization via structure predictors ("hallucination"). We argue that this is a false dichotomy and propose Proteina-Complexa, a novel fully atomistic binder generation method unifying both paradigms. We extend recent flow-based latent protein generation architectures and leverage the domain-domain interactions of monomeric computationally predicted protein structures to construct Teddymer, a new large-scale dataset of synthetic binder-target pairs for pretraining. Combined with high-quality experimental multimers, this enables training a strong base model. We then perform inference-time optimization with this generative prior, unifying the strengths of previously distinct generative and hallucination methods. Proteina-Complexa sets a new state of the art in computational binder design benchmarks: it delivers markedly higher in-silico success rates than existing generative approaches, and our novel test-time optimization strategies greatly outperform previous hallucination methods under normalized compute budgets. We also demonstrate interface hydrogen bond optimization, fold class-guided binder generation, and extensions to small molecule targets and enzyme design tasks, again surpassing prior methods. Code, models and new data will be publicly released.

Accurate prediction of protein-ligand binding poses is crucial for structure-based drug design, yet existing methods struggle to balance speed, accuracy, and physical plausibility. We introduce Matcha, a novel molecular docking pipeline that combines multi-stage flow matching with learned scoring and physical validity filtering. Our approach consists of three sequential stages applied consecutively to refine docking predictions, each implemented as a flow matching model operating on appropriate geometric spaces (R^3, SO(3), and SO(2)). We enhance the prediction quality through a dedicated scoring model and apply unsupervised physical validity filters to eliminate unrealistic poses. Compared to various approaches, Matcha demonstrates superior performance on Astex and PDBbind test sets in terms of docking success rate and physical plausibility. Moreover, our method works approximately 25 times faster than modern large-scale co-folding models. The model weights and inference code to reproduce our results are available at https://github.com/LigandPro/Matcha.

Consistency and reliability are crucial for conducting AI research. Many famous research fields, such as object detection, have been compared and validated with solid benchmark frameworks. After AlphaFold2, the protein folding task has entered a new phase, and many methods are proposed based on the component of AlphaFold2. The importance of a unified research framework in protein folding contains implementations and benchmarks to consistently and fairly compare various approaches. To achieve this, we present Solvent, an protein folding framework that supports significant components of state-of-th-arts models in the manner of off-the-shelf interface Solvent contains different models implemented in a unified codebase and supports training and evaluation for defined models on the same dataset. We benchmark well-known algorithms and their components and provide experiments that give helpful insights into the protein structure modeling field. We hope that Solvent will increase the reliability and consistency of proposed models and gives efficiency in both speed and costs, resulting in acceleration on protein folding modeling research. The code is available at https://github.com/kakaobrain/solvent, and the project will continue to be developed.

Quantum computing has gained a lot of attention recently, and scientists have seen potential applications in this field using quantum computing for Cryptography and Communication to Machine Learning and Healthcare. Protein folding has been one of the most interesting areas to study, and it is also one of the biggest problems of biochemistry. Each protein folds distinctively, and the difficulty of finding its stable shape rapidly increases with an increase in the number of amino acids in the chain. A moderate protein has about 100 amino acids, and the number of combinations one needs to verify to find the stable structure is enormous. At some point, the number of these combinations will be so vast that classical computers cannot even attempt to solve them. In this paper, we examine how this problem can be solved with the help of quantum computing using two different algorithms, Variational Quantum Eigensolver (VQE) and Quantum Approximate Optimization Algorithm (QAOA), using Qiskit Nature. We compare the results of different quantum hardware and simulators and check how error mitigation affects the performance. Further, we make comparisons with SoTA algorithms and evaluate the reliability of the method.

The structure-function relationship is at the heart of biology and major protein deformations are correlated to specific functions. In the case of heme proteins, doming is associated with the respiratory function in hemoglobin and myoglobin, while ruffling has been correlated with electron transfer processes, such as in the case of Cytochrome c (Cyt c). The latter has indeed evolved to become an important electron transfer protein in humans. In its ferrous form, it undergoes ligand release and doming upon photoexcitation, but its ferric form does not release the distal ligand, while the return to the ground state has been attributed to thermal relaxation. Here, by combining femtosecond Fe K-edge X-ray absorption near-edge structure (XANES) studies and femtosecond Fe Kalpha and Kbeta X-ray emission spectroscopy (XES), we demonstrate that the photocycle of ferric Cyt c is entirely due to a cascade among excited spin states of the Iron ion, causing the ferric heme to undergo doming, which we identify for the first time. We also argue that this pattern is common to all ferric haems, raising the question of the biological relevance of doming in such proteins.

The rapid evolution of generative models has unlocked new potentials in protein binder design, a pivotal task in structural biology, by facilitating end-to-end generation via joint sequence-structure modeling or hallucination. However, existing approaches are predominantly implemented under a single-target, single-state assumption, limiting their ability to model multi-target or multi-state interactions required for advanced function-oriented protein design. Here, we introduce Chamaileon, which unifies multi-target and multi-state binder design by formulating the problem as cross-context binding landscape modeling. The framework is underpinned by a training paradigm termed In-Context Complex Co-Design (I3CD) for context-aware sequence-structure co-modeling. During inference, we employ Mixture-of-Paths Sampling (MoPS), a scalable strategy that optimizes a single sequence across contexts while alleviating the scarcity of high-quality multi-conformational paired data. Extensive evaluation on our newly constructed benchmark, CROSS, demonstrates that Chamaileon effectively generates sequences adaptable to diverse conformational landscapes and multi-target requirements. The code is available on https://github.com/caohengyuan/Chamaileon.

Elucidating quantum coherence effects and geometrical factors for efficient energy transfer in photosynthesis has the potential to uncover non-classical design principles for advanced organic materials. We study energy transfer in a linear light-harvesting model to reveal that dimerized geometries with strong electronic coherences within donor and acceptor pairs exhibit significantly improved efficiency, which is in marked contrast to predictions of the classical F\"orster theory. We reveal that energy tuning due to coherent delocalization of photoexcitations is mainly responsible for the efficiency optimization. This coherence-assisted energy-tuning mechanism also explains the energetics and chlorophyll arrangements in the widely-studied Fenna-Matthews-Olson complex. We argue that a clustered network with rapid energy relaxation among donors and resonant energy transfer from donor to acceptor states provides a basic formula for constructing efficient light-harvesting systems, and the general principles revealed here can be generalized to larger systems and benefit future innovation of efficient molecular light-harvesting materials.