Daily Papers

The last few years have seen the development of numerous deep learning-based protein-ligand docking methods. They offer huge promise in terms of speed and accuracy. However, despite claims of state-of-the-art performance in terms of crystallographic root-mean-square deviation (RMSD), upon closer inspection, it has become apparent that they often produce physically implausible molecular structures. It is therefore not sufficient to evaluate these methods solely by RMSD to a native binding mode. It is vital, particularly for deep learning-based methods, that they are also evaluated on steric and energetic criteria. We present PoseBusters, a Python package that performs a series of standard quality checks using the well-established cheminformatics toolkit RDKit. Only methods that both pass these checks and predict native-like binding modes should be classed as having "state-of-the-art" performance. We use PoseBusters to compare five deep learning-based docking methods (DeepDock, DiffDock, EquiBind, TankBind, and Uni-Mol) and two well-established standard docking methods (AutoDock Vina and CCDC Gold) with and without an additional post-prediction energy minimisation step using a molecular mechanics force field. We show that both in terms of physical plausibility and the ability to generalise to examples that are distinct from the training data, no deep learning-based method yet outperforms classical docking tools. In addition, we find that molecular mechanics force fields contain docking-relevant physics missing from deep-learning methods. PoseBusters allows practitioners to assess docking and molecular generation methods and may inspire new inductive biases still required to improve deep learning-based methods, which will help drive the development of more accurate and more realistic predictions.

Predicting the binding structure of a small molecule ligand to a protein -- a task known as molecular docking -- is critical to drug design. Recent deep learning methods that treat docking as a regression problem have decreased runtime compared to traditional search-based methods but have yet to offer substantial improvements in accuracy. We instead frame molecular docking as a generative modeling problem and develop DiffDock, a diffusion generative model over the non-Euclidean manifold of ligand poses. To do so, we map this manifold to the product space of the degrees of freedom (translational, rotational, and torsional) involved in docking and develop an efficient diffusion process on this space. Empirically, DiffDock obtains a 38% top-1 success rate (RMSD<2A) on PDBBind, significantly outperforming the previous state-of-the-art of traditional docking (23%) and deep learning (20%) methods. Moreover, while previous methods are not able to dock on computationally folded structures (maximum accuracy 10.4%), DiffDock maintains significantly higher precision (21.7%). Finally, DiffDock has fast inference times and provides confidence estimates with high selective accuracy.

Docking is a crucial component in drug discovery aimed at predicting the binding conformation and affinity between small molecules and target proteins. ML-based docking has recently emerged as a prominent approach, outpacing traditional methods like DOCK and AutoDock Vina in handling the growing scale and complexity of molecular libraries. However, the availability of comprehensive and user-friendly datasets for training and benchmarking ML-based docking algorithms remains limited. We introduce Smiles2Dock, an open large-scale multi-task dataset for molecular docking. We created a framework combining P2Rank and AutoDock Vina to dock 1.7 million ligands from the ChEMBL database against 15 AlphaFold proteins, giving us more than 25 million protein-ligand binding scores. The dataset leverages a wide range of high-accuracy AlphaFold protein models, encompasses a diverse set of biologically relevant compounds and enables researchers to benchmark all major approaches for ML-based docking such as Graph, Transformer and CNN-based methods. We also introduce a novel Transformer-based architecture for docking scores prediction and set it as an initial benchmark for our dataset. Our dataset and code are publicly available to support the development of novel ML-based methods for molecular docking to advance scientific research in this field.

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.

Molecular docking is an important tool for structure-based drug design, accelerating the efficiency of drug development. Complex and dynamic binding processes between proteins and small molecules require searching and sampling over a wide spatial range. Traditional docking by searching for possible binding sites and conformations is computationally complex and results poorly under blind docking. Quantum-inspired algorithms combining quantum properties and annealing show great advantages in solving combinatorial optimization problems. Inspired by this, we achieve an improved in blind docking by using quantum-inspired combined with gradients learned by deep learning in the encoded molecular space. Numerical simulation shows that our method outperforms traditional docking algorithms and deep learning-based algorithms over 10\%. Compared to the current state-of-the-art deep learning-based docking algorithm DiffDock, the success rate of Top-1 (RMSD<2) achieves an improvement from 33\% to 35\% in our same setup. In particular, a 6\% improvement is realized in the high-precision region(RMSD<1) on molecules data unseen in DiffDock, which demonstrates the well-generalized of our method.

Motivation: Ab initio protein docking represents a major challenge for optimizing a noisy and costly "black box"-like function in a high-dimensional space. Despite progress in this field, there is no docking method available for rigorous uncertainty quantification (UQ) of its solution quality (e.g. interface RMSD or iRMSD). Results: We introduce a novel algorithm, Bayesian Active Learning (BAL), for optimization and UQ of such black-box functions and flexible protein docking. BAL directly models the posterior distribution of the global optimum (or native structures for protein docking) with active sampling and posterior estimation iteratively feeding each other. Furthermore, we use complex normal modes to represent a homogeneous Euclidean conformation space suitable for high-dimension optimization and construct funnel-like energy models for encounter complexes. Over a protein docking benchmark set and a CAPRI set including homology docking, we establish that BAL significantly improve against both starting points by rigid docking and refinements by particle swarm optimization, providing for one third targets a top-3 near-native prediction. BAL also generates tight confidence intervals with half range around 25% of iRMSD and confidence level at 85%. Its estimated probability of a prediction being native or not achieves binary classification AUROC at 0.93 and AUPRC over 0.60 (compared to 0.14 by chance); and also found to help ranking predictions. To the best of our knowledge, this study represents the first uncertainty quantification solution for protein docking, with theoretical rigor and comprehensive assessment. Source codes are available at https://github.com/Shen-Lab/BAL.

Molecular docking is a key computational tool utilized to predict the binding conformations of small molecules to protein targets, which is fundamental in the design of novel drugs. Despite recent advancements in geometric deep learning-based approaches leading to improvements in blind docking efficiency, these methods have encountered notable challenges, such as limited generalization performance on unseen proteins, the inability to concurrently address the settings of blind docking and site-specific docking, and the frequent occurrence of physical implausibilities such as inter-molecular steric clash. In this study, we introduce DeltaDock, a robust and versatile framework designed for efficient molecular docking to overcome these challenges. DeltaDock operates in a two-step process: rapid initial complex structures sampling followed by multi-scale iterative refinement of the initial structures. In the initial stage, to sample accurate structures with high efficiency, we develop a ligand-dependent binding site prediction model founded on large protein models and graph neural networks. This model is then paired with GPU-accelerated sampling algorithms. The sampled structures are updated using a multi-scale iterative refinement module that captures both protein-ligand atom-atom interactions and residue-atom interactions in the following stage. Distinct from previous geometric deep learning methods that are conditioned on the blind docking setting, DeltaDock demonstrates superior performance in both blind docking and site-specific docking settings. Comprehensive experimental results reveal that DeltaDock consistently surpasses baseline methods in terms of docking accuracy. Furthermore, it displays remarkable generalization capabilities and proficiency for predicting physically valid structures, thereby attesting to its robustness and reliability in various scenarios.

The regulation of various cellular processes heavily relies on the protein complexes within a living cell, necessitating a comprehensive understanding of their three-dimensional structures to elucidate the underlying mechanisms. While neural docking techniques have exhibited promising outcomes in binary protein docking, the application of advanced neural architectures to multimeric protein docking remains uncertain. This study introduces SyNDock, an automated framework that swiftly assembles precise multimeric complexes within seconds, showcasing performance that can potentially surpass or be on par with recent advanced approaches. SyNDock possesses several appealing advantages not present in previous approaches. Firstly, SyNDock formulates multimeric protein docking as a problem of learning global transformations to holistically depict the placement of chain units of a complex, enabling a learning-centric solution. Secondly, SyNDock proposes a trainable two-step SE(3) algorithm, involving initial pairwise transformation and confidence estimation, followed by global transformation synchronization. This enables effective learning for assembling the complex in a globally consistent manner. Lastly, extensive experiments conducted on our proposed benchmark dataset demonstrate that SyNDock outperforms existing docking software in crucial performance metrics, including accuracy and runtime. For instance, it achieves a 4.5% improvement in performance and a remarkable millionfold acceleration in speed.

Accurate blind docking has the potential to lead to new biological breakthroughs, but for this promise to be realized, docking methods must generalize well across the proteome. Existing benchmarks, however, fail to rigorously assess generalizability. Therefore, we develop DockGen, a new benchmark based on the ligand-binding domains of proteins, and we show that existing machine learning-based docking models have very weak generalization abilities. We carefully analyze the scaling laws of ML-based docking and show that, by scaling data and model size, as well as integrating synthetic data strategies, we are able to significantly increase the generalization capacity and set new state-of-the-art performance across benchmarks. Further, we propose Confidence Bootstrapping, a new training paradigm that solely relies on the interaction between diffusion and confidence models and exploits the multi-resolution generation process of diffusion models. We demonstrate that Confidence Bootstrapping significantly improves the ability of ML-based docking methods to dock to unseen protein classes, edging closer to accurate and generalizable blind docking methods.

The study of rigid protein-protein docking plays an essential role in a variety of tasks such as drug design and protein engineering. Recently, several learning-based methods have been proposed for the task, exhibiting much faster docking speed than those computational methods. In this paper, we propose a novel learning-based method called ElliDock, which predicts an elliptic paraboloid to represent the protein-protein docking interface. To be specific, our model estimates elliptic paraboloid interfaces for the two input proteins respectively, and obtains the roto-translation transformation for docking by making two interfaces coincide. By its design, ElliDock is independently equivariant with respect to arbitrary rotations/translations of the proteins, which is an indispensable property to ensure the generalization of the docking process. Experimental evaluations show that ElliDock achieves the fastest inference time among all compared methods and is strongly competitive with current state-of-the-art learning-based models such as DiffDock-PP and Multimer particularly for antibody-antigen docking.

We introduce IntFold, a controllable foundation model for both general and specialized biomolecular structure prediction. IntFold demonstrates predictive accuracy comparable to the state-of-the-art AlphaFold3, while utilizing a superior customized attention kernel. Beyond standard structure prediction, IntFold can be adapted to predict allosteric states, constrained structures, and binding affinity through the use of individual adapters. Furthermore, we introduce a novel confidence head to estimate docking quality, offering a more nuanced assessment for challenging targets such as antibody-antigen complexes. Finally, we share insights gained during the training process of this computationally intensive model.

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.

Molecular docking is critical to structure-based virtual screening, yet the throughput of such workflows is limited by the expensive optimization of scoring functions involved in most docking algorithms. We explore how machine learning can accelerate this process by learning a scoring function with a functional form that allows for more rapid optimization. Specifically, we define the scoring function to be the cross-correlation of multi-channel ligand and protein scalar fields parameterized by equivariant graph neural networks, enabling rapid optimization over rigid-body degrees of freedom with fast Fourier transforms. The runtime of our approach can be amortized at several levels of abstraction, and is particularly favorable for virtual screening settings with a common binding pocket. We benchmark our scoring functions on two simplified docking-related tasks: decoy pose scoring and rigid conformer docking. Our method attains similar but faster performance on crystal structures compared to the widely-used Vina and Gnina scoring functions, and is more robust on computationally predicted structures. Code is available at https://github.com/bjing2016/scalar-fields.

Modeling the interaction between proteins and ligands and accurately predicting their binding structures is a critical yet challenging task in drug discovery. Recent advancements in deep learning have shown promise in addressing this challenge, with sampling-based and regression-based methods emerging as two prominent approaches. However, these methods have notable limitations. Sampling-based methods often suffer from low efficiency due to the need for generating multiple candidate structures for selection. On the other hand, regression-based methods offer fast predictions but may experience decreased accuracy. Additionally, the variation in protein sizes often requires external modules for selecting suitable binding pockets, further impacting efficiency. In this work, we propose FABind, an end-to-end model that combines pocket prediction and docking to achieve accurate and fast protein-ligand binding. FABind incorporates a unique ligand-informed pocket prediction module, which is also leveraged for docking pose estimation. The model further enhances the docking process by incrementally integrating the predicted pocket to optimize protein-ligand binding, reducing discrepancies between training and inference. Through extensive experiments on benchmark datasets, our proposed FABind demonstrates strong advantages in terms of effectiveness and efficiency compared to existing methods. Our code is available at https://github.com/QizhiPei/FABind

Hall-effect thrusters (HETs) are widely used for modern near-earth spacecraft propulsion and are vital for future deep-space missions. Methods of modeling HETs are developing rapidly. However, such methods are not yet precise enough and cannot reliably predict the parameters of a newly designed thruster, mostly due to the enormous computational cost of a HET plasma simulation. Another approach is to use scaling techniques based on available experimental data. This paper proposes an approach for scaling HETs using neural networks and other modern machine learning methods. The new scaling model was built with information from an extensive database of HET parameters collected from published papers. Predictions of the new scaling model are valid for the operating parameters domain covered by the database. During the design, this model can help HET developers estimate the performance of a newly-designed thruster. At the stage of experimental research, the model can be used to compare the achieved characteristics of the studied thruster with the level obtained by other developers. A comparison with the state-of-the-art HET scaling model is also presented.

Unmodeled aerodynamic disturbances pose a key challenge for multirotor flight when multiple vehicles are in close proximity to each other. However, certain missions require two multirotors to approach each other within 1-2 body-lengths of each other and hold formation -- we consider one such practical instance: vertically docking two multirotors in the air. In this leader-follower setting, the follower experiences significant downwash interference from the leader in its final docking stages. To compensate for this, we employ a learnt downwash model online within an optimal feedback controller to accurately track a docking maneuver and then hold formation. Through real-world flights with different maneuvers, we demonstrate that this compensation is crucial for reducing the large vertical separation otherwise required by conventional/naive approaches. Our evaluations show a tracking error of less than 0.06m for the follower (a 3-4x reduction) when approaching vertically within two body-lengths of the leader. Finally, we deploy the complete system to effect a successful physical docking between two airborne multirotors in a single smooth planned trajectory.

Hall effect thrusters are one of the most versatile and popular electric propulsion systems for space use. Industry trends towards interplanetary missions arise advances in design development of such propulsion systems. It is understood that correct sizing of discharge channel in Hall effect thruster impact performance greatly. Since the complete physics model of such propulsion system is not yet optimized for fast computations and design iterations, most thrusters are being designed using so-called scaling laws. But this work focuses on rather novel approach, which is outlined less frequently than ordinary scaling design approach in literature. Using deep machine learning it is possible to create predictive performance model, which can be used to effortlessly get design of required hall thruster with required characteristics using way less computational power than design from scratch and way more flexible than usual scaling approach.