Retrieval-augmented generation (RAG) has effectively mitigated the hallucination problem of large language models (LLMs). However, the difficulty of aligning the retriever with the LLMs' diverse knowledge preferences inevitably poses a challenge in developing a reliable RAG system. To address this issue, we propose DPA-RAG, a universal framework designed to align diverse knowledge preferences within RAG systems. Specifically, we initially introduce a preference knowledge construction pipeline and incorporate five novel query augmentation strategies to alleviate preference data scarcity. Based on preference data, DPA-RAG accomplishes both external and internal preference alignment: 1) It jointly integrates pairwise, pointwise, and contrastive preference alignment abilities into the reranker, achieving external preference alignment among RAG components. 2) It further introduces a pre-aligned stage before vanilla Supervised Fine-tuning (SFT), enabling LLMs to implicitly capture knowledge aligned with their reasoning preferences, achieving LLMs' internal alignment. Experimental results across four knowledge-intensive QA datasets demonstrate that DPA-RAG outperforms all baselines and seamlessly integrates both black-box and open-sourced LLM readers. Further qualitative analysis and discussions provide empirical guidance for achieving reliable RAG systems. Our code and example dataset are available at https://github.com/dongguanting/DPA-RAG.

Protein-ligand interaction prediction presents a significant challenge in drug design. Numerous machine learning and deep learning (DL) models have been developed to accurately identify docking poses of ligands and active compounds against specific targets. However, current models often suffer from inadequate accuracy or lack practical physical significance in their scoring systems. In this research paper, we introduce IGModel, a novel approach that utilizes the geometric information of protein-ligand complexes as input for predicting the root mean square deviation of docking poses and the binding strength (pKd, the negative value of the logarithm of binding affinity) within the same prediction framework. This ensures that the output scores carry intuitive meaning. We extensively evaluate the performance of IGModel on various docking power test sets, including the CASF-2016 benchmark, PDBbind-CrossDocked-Core and DISCO set, consistently achieving state-of-the-art accuracies. Furthermore, we assess IGModel's generalizability and robustness by evaluating it on unbiased test sets and sets containing target structures generated by AlphaFold2. The exceptional performance of IGModel on these sets demonstrates its efficacy. Additionally, we visualize the latent space of protein-ligand interactions encoded by IGModel and conduct interpretability analysis, providing valuable insights. This study presents a novel framework for DL-based prediction of protein-ligand interactions, contributing to the advancement of this field. The IGModel is available at GitHub repository https://github.com/zchwang/IGModel.

MOTIVATION: Molecular docking is an invaluable computational tool with broad applications in computer-aided drug design and enzyme engineering. However, current molecular docking tools are typically implemented in languages such as C++ for calculation speed, which lack flexibility and user-friendliness for further development. Moreover, validating the effectiveness of external scoring functions for molecular docking and screening within these frameworks is challenging, and implementing more efficient sampling strategies is not straightforward. RESULTS: To address these limitations, we have developed an open-source molecular docking framework, OpenDock, based on Python and PyTorch. This framework supports the integration of multiple scoring functions; some can be utilized during molecular docking and pose optimization, while others can be used for post-processing scoring. In terms of sampling, the current version of this framework supports simulated annealing and Monte Carlo optimization. Additionally, it can be extended to include methods such as genetic algorithms and particle swarm optimization for sampling docking poses and protein side chain orientations. Distance constraints are also implemented to enable covalent docking, restricted docking or distance map constraints guided pose sampling. Overall, this framework serves as a valuable tool in drug design and enzyme engineering, offering significant flexibility for most protein-ligand modelling tasks. AVAILABILITY AND IMPLEMENTATION: OpenDock is publicly available at: https://github.com/guyuehuo/opendock.

The objective of few-shot named entity recognition is to identify named entities with limited labeled instances. Previous works have primarily focused on optimizing the traditional token-wise classification framework, while neglecting the exploration of information based on NER data characteristics. To address this issue, we propose a Multi-Task Semantic Decomposition Framework via Joint Task-specific Pre-training (MSDP) for few-shot NER. Drawing inspiration from demonstration-based and contrastive learning, we introduce two novel pre-training tasks: Demonstration-based Masked Language Modeling (MLM) and Class Contrastive Discrimination. These tasks effectively incorporate entity boundary information and enhance entity representation in Pre-trained Language Models (PLMs). In the downstream main task, we introduce a multi-task joint optimization framework with the semantic decomposing method, which facilitates the model to integrate two different semantic information for entity classification. Experimental results of two few-shot NER benchmarks demonstrate that MSDP consistently outperforms strong baselines by a large margin. Extensive analyses validate the effectiveness and generalization of MSDP.

Few-shot named entity recognition (NER) aims at identifying named entities based on only few labeled instances. Most existing prototype-based sequence labeling models tend to memorize entity mentions which would be easily confused by close prototypes. In this paper, we proposed a Prototypical Semantic Decoupling method via joint Contrastive learning (PSDC) for few-shot NER. Specifically, we decouple class-specific prototypes and contextual semantic prototypes by two masking strategies to lead the model to focus on two different semantic information for inference. Besides, we further introduce joint contrastive learning objectives to better integrate two kinds of decoupling information and prevent semantic collapse. Experimental results on two few-shot NER benchmarks demonstrate that PSDC consistently outperforms the previous SOTA methods in terms of overall performance. Extensive analysis further validates the effectiveness and generalization of PSDC.

In real dialogue scenarios, the existing slot filling model, which tends to memorize entity patterns, has a significantly reduced generalization facing Out-of-Vocabulary (OOV) problems. To address this issue, we propose an OOV robust slot filling model based on multi-level data augmentations to solve the OOV problem from both word and slot perspectives. We present a unified contrastive learning framework, which pull representations of the origin sample and augmentation samples together, to make the model resistant to OOV problems. We evaluate the performance of the model from some specific slots and carefully design test data with OOV word perturbation to further demonstrate the effectiveness of OOV words. Experiments on two datasets show that our approach outperforms the previous sota methods in terms of both OOV slots and words.

The recently reported machine learning- or deep learning-based scoring functions (SFs) have shown exciting performance in predicting protein-ligand binding affinities with fruitful application prospects. However, the differentiation between highly similar ligand conformations, including the native binding pose (the global energy minimum state), remains challenging that could greatly enhance the docking. In this work, we propose a fully differentiable, end-to-end framework for ligand pose optimization based on a hybrid SF called DeepRMSD+Vina combined with a multi-layer perceptron (DeepRMSD) and the traditional AutoDock Vina SF. The DeepRMSD+Vina, which combines (1) the root mean square deviation (RMSD) of the docking pose with respect to the native pose and (2) the AutoDock Vina score, is fully differentiable; thus is capable of optimizing the ligand binding pose to the energy-lowest conformation. Evaluated by the CASF-2016 docking power dataset, the DeepRMSD+Vina reaches a success rate of 94.4%, which outperforms most reported SFs to date. We evaluated the ligand conformation optimization framework in practical molecular docking scenarios (redocking and cross-docking tasks), revealing the high potentialities of this framework in drug design and discovery. Structural analysis shows that this framework has the ability to identify key physical interactions in protein-ligand binding, such as hydrogen-bonding. Our work provides a paradigm for optimizing ligand conformations based on deep learning algorithms. The DeepRMSD+Vina model and the optimization framework are available at GitHub repository https://github.com/zchwang/DeepRMSD-Vina_Optimization.

Most existing slot filling models tend to memorize inherent patterns of entities and corresponding contexts from training data. However, these models can lead to system failure or undesirable outputs when being exposed to spoken language perturbation or variation in practice. We propose a perturbed semantic structure awareness transferring method for training perturbation-robust slot filling models. Specifically, we introduce two MLM-based training strategies to respectively learn contextual semantic structure and word distribution from unsupervised language perturbation corpus. Then, we transfer semantic knowledge learned from upstream training procedure into the original samples and filter generated data by consistency processing. These procedures aims to enhance the robustness of slot filling models. Experimental results show that our method consistently outperforms the previous basic methods and gains strong generalization while preventing the model from memorizing inherent patterns of entities and contexts.

Scoring functions are important components in molecular docking for structure-based drug discovery. Traditional scoring functions, generally empirical- or force field-based, are robust and have proven to be useful for identifying hits and lead optimizations. Although multiple highly accurate deep learning- or machine learning-based scoring functions have been developed, their direct applications for docking and screening are limited. We describe a novel strategy to develop a reliable protein-ligand scoring function by augmenting the traditional scoring function Vina score using a correction term (OnionNet-SFCT). The correction term is developed based on an AdaBoost random forest model, utilizing multiple layers of contacts formed between protein residues and ligand atoms. In addition to the Vina score, the model considerably enhances the AutoDock Vina prediction abilities for docking and screening tasks based on different benchmarks (such as cross-docking dataset, CASF-2016, DUD-E and DUD-AD). Furthermore, our model could be combined with multiple docking applications to increase pose selection accuracies and screening abilities, indicating its wide usage for structure-based drug discoveries. Furthermore, in a reverse practice, the combined scoring strategy successfully identified multiple known receptors of a plant hormone. To summarize, the results show that the combination of data-driven model (OnionNet-SFCT) and empirical scoring function (Vina score) is a good scoring strategy that could be useful for structure-based drug discoveries and potentially target fishing in future.