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Motivation: Generating molecules of high quality and drug-likeness in the vast chemical space is a big challenge in the drug discovery. Most existing molecule generative methods focus on diversity and novelty of molecules, but ignoring drug potentials of the generated molecules during the generation process. Results: In this study, we present a novel de novo multiobjective quality assessment-based drug design approach (QADD), which integrates an iterative refinement framework with a novel graph-based molecular quality assessment model on drug potentials. QADD designs a multiobjective deep reinforcement learning pipeline to generate molecules with multiple desired properties iteratively, where a graph neural network-based model for accurate molecular quality assessment on drug potentials is introduced to guide molecule generation. Experimental results show that QADD can jointly optimize multiple molecular properties with a promising performance and the quality assessment module is capable of guiding the generated molecules with high drug potentials. Furthermore, applying QADD to generate novel molecules binding to a biological target protein DRD2 also demonstrates the algorithm's efficacy. Availability and implementation: QADD is freely available online for academic use at https://github.com/yifang000/QADD or http://www.csbio.sjtu.edu.cn/bioinf/QADD. [ABSTRACT FROM AUTHOR]

Motivation Coiled-coil is composed of two or more helices that are wound around each other. It widely exists in proteins and has been discovered to play a variety of critical roles in biology processes. Generally, there are three types of structural features in coiled-coil: coiled-coil domain (CCD), oligomeric state and register. However, most of the existing computational tools only focus on one of them. Results Here, we describe a new deep learning model, CoCoPRED, which is based on convolutional layers, bidirectional long short-term memory, and attention mechanism. It has three networks, i.e. CCD network, oligomeric state network, and register network, corresponding to the three types of structural features in coiled-coil. This means CoCoPRED has the ability of fulfilling comprehensive prediction for coiled-coil proteins. Through the 5-fold cross-validation experiment, we demonstrate that CoCoPRED can achieve better performance than the state-of-the-art models on both CCD prediction and oligomeric state prediction. Further analysis suggests the CCD prediction may be a performance indicator of the oligomeric state prediction in CoCoPRED. The attention heads in CoCoPRED indicate that registers a , b and e are more crucial for the oligomeric state prediction. Availability and implementation CoCoPRED is available at http://www.csbio.sjtu.edu.cn/bioinf/CoCoPRED. The datasets used in this research can also be downloaded from the website. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Motivation Reverse engineering of gene regulatory networks (GRNs) has long been an attractive research topic in system biology. Computational prediction of gene regulatory interactions has remained a challenging problem due to the complexity of gene expression and scarce information resources. The high-throughput spatial gene expression data, like in situ hybridization images that exhibit temporal and spatial expression patterns, has provided abundant and reliable information for the inference of GRNs. However, computational tools for analyzing the spatial gene expression data are highly underdeveloped. Results In this study, we develop a new method for identifying gene regulatory interactions from gene expression images, called ConGRI. The method is featured by a contrastive learning scheme and deep Siamese convolutional neural network architecture, which automatically learns high-level feature embeddings for the expression images and then feeds the embeddings to an artificial neural network to determine whether or not the interaction exists. We apply the method to a Drosophila embryogenesis dataset and identify GRNs of eye development and mesoderm development. Experimental results show that ConGRI outperforms previous traditional and deep learning methods by a large margin, which achieves accuracies of 76.7% and 68.7% for the GRNs of early eye development and mesoderm development, respectively. It also reveals some master regulators for Drosophila eye development. Availabilityand implementation https://github.com/lugimzheng/ConGRI. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Motivation The tissue atlas of the human protein atlas (HPA) houses immunohistochemistry (IHC) images visualizing the protein distribution from the tissue level down to the cell level, which provide an important resource to study human spatial proteome. Especially, the protein subcellular localization patterns revealed by these images are helpful for understanding protein functions, and the differential localization analysis across normal and cancer tissues lead to new cancer biomarkers. However, computational tools for processing images in this database are highly underdeveloped. The recognition of the localization patterns suffers from the variation in image quality and the difficulty in detecting microscopic targets. Results We propose a deep multi-instance multi-label model, ImPLoc, to predict the subcellular locations from IHC images. In this model, we employ a deep convolutional neural network-based feature extractor to represent image features, and design a multi-head self-attention encoder to aggregate multiple feature vectors for subsequent prediction. We construct a benchmark dataset of 1186 proteins including 7855 images from HPA and 6 subcellular locations. The experimental results show that ImPLoc achieves significant enhancement on the prediction accuracy compared with the current computational methods. We further apply ImPLoc to a test set of 889 proteins with images from both normal and cancer tissues, and obtain 8 differentially localized proteins with a significance level of 0.05. Availability and implementation https://github.com/yl2019lw/ImPloc. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Motivation Systematic and comprehensive analysis of protein subcellular location as a critical part of proteomics ('location proteomics') has been studied for many years, but annotating protein subcellular locations and understanding variation of the location patterns across various cell types and states is still challenging. Results In this work, we used immunohistochemistry images from the Human Protein Atlas as the source of subcellular location information, and built classification models for the complex protein spatial distribution in normal and cancerous tissues. The models can automatically estimate the fractions of protein in different subcellular locations, and can help to quantify the changes of protein distribution from normal to cancer tissues. In addition, we examined the extent to which different annotated protein pathways and complexes showed similarity in the locations of their member proteins, and then predicted new potential proteins for these networks. Availability and implementation The dataset and code are available at: www.csbio.sjtu.edu.cn/bioinf/complexsubcellularpatterns. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Motivation Protein structure refinement is an important step of protein structure prediction. Existing approaches have generally used a single scoring function combined with Monte Carlo method or Molecular Dynamics algorithm. The one-dimension optimization of a single energy function may take the structure too far away without a constraint. The basic motivation of our study is to reduce the bias problem caused by minimizing only a single energy function due to the very diversity of different protein structures. Results We report a new Artificial Intelligence-based protein structure Refinement method called AIR. Its fundamental idea is to use multiple energy functions as multi-objectives in an effort to correct the potential inaccuracy from a single function. A multi-objective particle swarm optimization algorithm-based structure refinement is designed, where each structure is considered as a particle in the protocol. With the refinement iterations, the particles move around. The quality of particles in each iteration is evaluated by three energy functions, and the non-dominated particles are put into a set called Pareto set. After enough iteration times, particles from the Pareto set are screened and part of the top solutions are outputted as the final refined structures. The multi-objective energy function optimization strategy designed in the AIR protocol provides a different constraint view of the structure, by extending the one-dimension optimization to a new three-dimension space optimization driven by the multi-objective particle swarm optimization engine. Experimental results on CASP11, CASP12 refinement targets and blind tests in CASP 13 turn to be promising. Availability and implementation The AIR is available online at: www.csbio.sjtu.edu.cn/bioinf/AIR/. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Motivation: Inter-residue contacts in proteins have been widely acknowledged to be valuable for protein 3D structure prediction. Accurate prediction of long-range transmembrane inter-helix residue contacts can significantly improve the quality of simulated membrane protein models. Results: In this paper, we present an updated MemBrain predictor, which aims to predict transmembrane protein residue contacts. Our new model benefits from an efficient learning algorithm that can mine latent structural features, which exist in original feature space. The new MemBrain is a two-stage inter-helix contact predictor. The first stage takes sequence-based features as inputs and outputs coarse contact probabilities for each residue pair, which will be further fed into convolutional neural network together with predictions from three direct-coupling analysis approaches in the second stage. Experimental results on the training dataset show that our method achieves an average accuracy of 81.6% for the top L/5 predictions using a strict sequence-based jackknife cross-validation. Evaluated on the test dataset, MemBrain can achieve 79.4% prediction accuracy. Moreover, for the top L/5 predicted long-range loop contacts, the prediction performance can reach an accuracy of 56.4%. These results demonstrate that the new MemBrain is promising for transmembrane protein’s contact map prediction. [ABSTRACT FROM AUTHOR]

Motivation: There is a long-term interest in the challenging task of finding translocated and mislocated cancer biomarker proteins. Bioimages of subcellular protein distribution are new data sources which have attracted much attention in recent years because of their intuitive and detailed descriptions of protein distribution. However, automated methods in large-scale biomarker screening suffer significantly from the lack of subcellular location annotations for bioimages from cancer tissues. The transfer prediction idea of applying models trained on normal tissue proteins to predict the subcellular locations of cancerous ones is arbitrary because the protein distribution patterns may differ in normal and cancerous states. Results: We developed a new semi-supervised protocol that can use unlabeled cancer protein data in model construction by an iterative and incremental training strategy. Our approach enables us to selectively use the low-quality images in normal states to expand the training sample space and provides a general way for dealing with the small size of annotated images used together with large unannotated ones. Experiments demonstrate that the new semi-supervised protocol can result in improved accuracy and sensitivity of subcellular location difference detection. [ABSTRACT FROM AUTHOR]