AI-Driven Prediction of Enzyme Structure and Function and Its Applications

BASIL is a course‐based undergraduate research experience (CURE) that focuses on enzyme function prediction. The Protein Data Bank (PDB) contains the structures of over 4000 proteins of unknown function and BASIL provides a basis to assign functions by combining in silico and in vitro analyses. The final BASIL module focuses on a kinetic analysis of the purified protein. In this study we investigate if the BASIL CURE promotes the development of student understanding of Michaelis‐Menten kinetics. Through content analysis of the written BASIL modules and inductive analysis of instructor interview transcripts, we have determined an “expert answer” that has been categorized into three overarching themes: the function of an enzyme is to convert a substrate to a product; the conversion of substrate to product can be tested with experimental assays; and data from assays can be visualized with a graph to characterize the kinetics of enzyme function. These ideal answer subthemes then were aligned with the course‐based undergraduate research abilities (CURAs) identified by Irby et al. (2018). We analyzed student research posters and coded semi‐structured interviews with students who have participated in BASIL at Ursinus College in order to compare them with the “expert answer”. Results suggest that students appear to understand the function of an enzyme and can interpret findings from an activity assay, yet they are lacking in a full understanding of the required data manipulation or underlying meaning of a graphical analysis of kinetics data. In the longer term, this research is aimed at informing improvements in the teaching, learning, and assessment of this area of the BASIL CURE. In particular, the findings will focus on addressing the various identified student difficulties so that the BASIL CURE can come closer to achieving its main goal of developing students as research scientists.Support or Funding InformationThis work was supported by the National Science Foundation under grants #1503811 & 1709805 for the Biochemistry Authentic Scientific Inquiry Lab (BASIL) CURE and #1346567 for the Advancing Competencies in Experimentation ‐ Biology (ACE‐Bio) Network. Any opinions, findings, and conclusions or recommendations expressed in this workshop are those of the authors and do not necessarily reflect the views of the National Science Foundation.Biochemistry Authentic Scientific Inquiry LabFigure 1

Characterizing enzyme sequences and identifying their active sites is a very important task. The current experimental methods are too expensive and labor intensive to handle the rapidly accumulating protein sequences and structure data. Thus accurate, high-throughput in silico methods for identifying catalytic residues and enzyme function prediction are much needed. In this paper, we propose a novel sequence-based catalytic domain prediction method using a sequence clustering and an information-theoretic approaches. The first step is to perform the sequence clustering analysis of enzyme sequences from the same functional category (those with the same EC label). The clustering analysis is used to handle the problem of widely varying sequence similarity levels in enzyme sequences. The clustering analysis constructs a sequence graph where nodes are enzyme sequences and edges are a pair of sequences with a certain degree of sequence similarity, and uses graph properties, such as biconnected components and articulation points, to generate sequence segments common to the enzyme sequences. Then amino acid subsequences in the common shared regions are aligned and then an information theoretic approach called aggregated column related scoring scheme is performed to highlight potential active sites in enzyme sequences. The aggregated information content scoring scheme is shown to be effective to highlight residues of active sites effectively. The proposed method of combining the clustering and the aggregated information content scoring methods was successful in highlighting known catalytic sites in enzymes of Escherichia coli K12 in terms of the Catalytic Site Atlas database. Our method is shown to be not only accurate in predicting potential active sites in the enzyme sequences but also computationally efficient since the clustering approach utilizes two graph properties that can be computed in linear to the number of edges in the sequence graph and computation of mutual information does not require much time. We believe that the proposed method can be useful for identifying active sites of enzyme sequences from many genome projects.

Course-based Undergraduate Research Experiences (CUREs) can be a very effective means to introduce a large number of students to research. CUREs are often an extension of the instructor's research, which may make them difficult to replicate in other settings because of differences in expertise or facilities. The BASIL (Biochemistry Authentic Scientific Inquiry Lab) CURE has evolved over the past 4 years as faculty members with different backgrounds, facilities, and campus cultures have all contributed to a robust curriculum focusing on enzyme function prediction that is suitable for implementation in a wide variety of academic settings. © 2019 International Union of Biochemistry and Molecular Biology, 47(5):498-505, 2019.

Recent advances in Graph Neural Networks (GNNs) have changed the landscape of modern graph analytics. The complexity of GNN training and the scalability challenges have also sparked interest from the systems community, with efforts to build systems that provide higher efficiency and schemes to reduce costs. However, we observe that many such systems basically "reinvent the wheel" of much work done in the database world on scalable graph analytics engines. Further, they often tightly couple the scalability treatments of graph data processing with that of GNN training, resulting in entangled complex problems and systems that often do not scale well on one of those axes. In this paper, we ask a fundamental question: How far can we push existing systems for scalable graph analytics and deep learning (DL) instead of building custom GNN systems? Are compromises inevitable on scalability and/or runtimes? We propose Lotan, the first scalable and optimized data system for full-batch GNN training with decoupled scaling that bridges the hitherto siloed worlds of graph analytics systems and DL systems. Lotan offers a series of technical innovations, including re-imagining GNN training as query plan-like dataflows, execution plan rewriting, optimized data movement between systems, a GNN-centric graph partitioning scheme, and the first known GNN model batching scheme. We prototyped Lotan on top of GraphX and PyTorch. An empirical evaluation using several real-world benchmark GNN workloads reveals a promising nuanced picture: Lotan significantly surpasses the scalability of state-of-the-art custom GNN systems, while often matching or being only slightly behind on time-to-accuracy metrics in some cases. We also show the impact of our system optimizations. Overall, our work shows that the GNN world can indeed benefit from building on top of scalable graph analytics engines. Lotan's new level of scalability can also empower new ML-oriented research on ever-larger graphs and GNNs.

Prunus mume "Langmei" is a relict tree species, which fruit has good medicinal value. To understand the biosynthesis pathway of citric acid, the Illumina HiSeq XTen high-throughput sequencing technology was used to get the transcriptome from "Langmei". A total of 38 936 unigenes were obtained by assembling the fruit transcripts, of which 28 311 unigenes were successfully annotated in public databases, 15 193 unigenes were mapped to 265 KEGG metabolic pathways, and 18 908 unigenes were classified into 59 GO functional subclasses, 103 unigenes encoding 15 key enzymes involved in citric acid synthesis pathway were identified and analyzed. The structural model of citrate synthetase in "Langmei" showed that it was a homodimer and the secondary structure of each monomer was mainly composed of alpha helixes. Moreover, the residues in the active site of the citrate synthetase were highly conserved. This study provides a valuable resource for identifying candidate genes involved in the citric acid biosynthesis pathway, and will promote the development and sustainable utilization of genetic resources of "Langmei".

Graph neural networks (GNNs) is an information - processing system that uses message passing among graph nodes. In recent years, GNN variants including graph attention network (GAT), graph convolutional network (GCN), and graph recurrent network (GRN) have shown revolutionary performance in computer vision applications using deep learning and artificial intelligence. These neural network model extensions, collect information in the form of graphs. GNN may be divided into three groups based on the challenges it solves: link prediction, node classification, graph classification. Machines can differentiate and recognise objects in image and video using standard CNNs. Extensive amount of research work needs to be done before robots can have same visual intuition as humans. GNN architectures, on the other hand, may be used to solve various image categorization and video challenges. The number of GNN applications in computer vision not limited, continues to expand. Human-object interaction, actin understanding, image categorization from a few shots and many more. In this paper use of GNN in image and video understanding, design aspects, architecture, applications and implementation challenges towards computer vision is described. GNN is a strong tool for analysing graph data and is still a relatively active area that needs further researches attention to solve many computer vision applications.

Heuristics are one of the most important tools to guide search to solve combinatorial problems. They are often specifically designed for one single problem and require both expertise and implementation work. Generic frameworks like SAT or CSP have developed heuristics that obey general principles like first fail or are able to learn and adapt from the exploration of the search tree like Dom/wDeg. In SAT, the classic VSIDS heuristic falls into both categories. The question of whether it is possible to learn from solving existing problems has been addressed for a long time by portfolio solvers where the best heuristic is chosen by Machine Learning from hand-crafted features, and more recently with Deep Learning by embedding this knowledge into a Graph Neural Network (GNN). In this paper, we build upon the latter category by proposing a new heuristic based on Deep Reinforcement Learning using two GNNs with adversarial rewards. We show that our method reduces the number of fails to get the first solution by more than 50% compared to MiniSat. This work shows the advantages of this type of techniques to extract structural and contextual knowledge from past solving experience.

AI-Driven molecule generation and bioactivity prediction: A multi-model approach combining VAE, graph and language-based neural networks.

The study of graph neural networks has revealed that they can unleash new applications in a variety of disciplines using such a basic process that we cannot imagine in the context of other deep learning designs. Many limitations limit their expressiveness, and researchers are working to overcome them to fully exploit the power of graph data. There are a number of publications that explore graph neural networks (GNNs) restrictions and bottlenecks, but the common thread that runs through them all is that they can all be traced back to message passing, which is the key technique we use to train our graph models. We outline the general GNN design pipeline in this study as well as discuss solutions to the over-smoothing problem, categorize the solutions, and identify open challenges for further research. Abbreviations: CGNN: Continuous Graph Neural Networks; CNN: Convolution NeuralNetwork; DeGNN: Decomposition Graph Neural Network; DGN: Directional GraphNetworks; DGN: Differentiable Group Normalization; DL: Deep Learning; EGAI:Enhancing GNNs by a High-quality Aggregation of Beneficial Information; GAT: GraphAttention Network; GCN: Graph Convolutional Network; GDC: Graph Drop Connect; GDR: Group Distance Ratio; GNN: Graph Neural Network; GRAND: GraphRandom Neural Networks; IIG: Instance Information Gain; MAD: Man AverageDistance; PDE-GCN: Partial Differential Equations-GCN; PTDNet: ParameterizedTopological Denoising network; TDGNN: Tree Decomposition Graph NeuralNetwork;

Node representation learning on attributed graphs-whose nodes are associated with rich attributes (e.g., texts and protein sequences)-plays a crucial role in many important downstream tasks. To encode the attributes and graph structures simultaneously, recent studies integrate pre-trained models with graph neural networks (GNNs), where pre-trained models serve as node encoders (NEs) to encode the attributes. As jointly training large NEs and GNNs on large-scale graphs suffers from severe scalability issues, many methods propose to train NEs and GNNs separately. Consequently, they do not take feature convolutions in GNNs into consideration in the training phase of NEs, leading to a significant learning bias relative to the joint training. To address this challenge, we propose an efficient label regularization technique, namely Label Deconvolution (LD), to alleviate the learning bias by a novel and highly scalable approximation to the inverse mapping of GNNs. The inverse mapping leads to an objective function that is equivalent to that by the joint training, while it can effectively incorporate GNNs in the training phase of NEs against the learning bias. More importantly, we show that LD converges to the optimal objective function values by the joint training under mild assumptions. Experiments demonstrate LD significantly outperforms state-of-the-art methods on Open Graph Benchmark datasets.

Past events have revealed that widespread blackouts are mostly a result of cascading failures in the power grid. Understanding the underlining mechanisms of cascading failures can help in developing strategies to minimize the risk of such events. Moreover, a real-time detection of precursors to cascading failures will help operators take measures to prevent their propagation. Currently, the well-established probabilistic and physics-based models of cascading failures offer low computational efficiency, hindering them to be used only as offline tools. In this work, we develop a data-driven methodology for online estimation of the risk of cascading failures. We utilize a physics-based cascading failure model to generate a cascading failure dataset considering different operating conditions and failure scenarios, thus obtaining a sample space covering a large set of power grid states that are labeled as safe or unsafe. We use the synthetic data to train deep learning architectures, namely Feed-forward Neural Networks (FNN) and Graph Neural Networks (GNN). With the development of GNNs, improved performance is achieved with graph-structured data, and GNNs can generalize to graphs of diverse sizes. A comparison between FNN and GNN is made and the GNNs inductive capability is demonstrated via test grids. Furthermore, we apply transfer learning to improve the performance of a pre-trained GNN model on power grids not seen in the training process. The GNN model shows accuracy and balanced accuracy above 96% on selected test datasets not used in the training. Conversely, the FNN shows accuracy above 85% and balanced accuracy above 81% on test datasets unseen during training. Overall, the GNN model is successful in determining, if one or several simultaneous outages result in a critical grid state, under specific grid operating conditions.

Deep learning on graphs is an upcoming area of study. This chapter provides an introduction to graph neural networks (GNNs), a type of neural network that is designed to process data represented in the form of graphs. First, it summarizes the explanation of deep learning on graphs. The fundamental concepts of graph neural networks, as well as GNN theories, are then explained. In this chapter, different types of graph neural network (GNN) are also explained. At the end, the applications of graph neural network where GNN is used and for what purpose it is going to be used are explained. This also explores the various applications of GNNs in fields such as social network analysis, recommendation systems, drug discovery, computer vision, and natural language processing. With the increasing prevalence of graph data, GNNs are becoming increasingly important and will likely continue to play a significant role in many fields in the future.

Traffic forecasting is a crucial aspect of modern Intelligent Transportation Systems (ITS) and the Internet of Vehicles (IoV), playing a vital role in improving the safety and efficiency of daily transportation activities. Despite the valuable contributions of traditional machine learning (ML) models and advanced deep learning (DL) techniques, there persist challenges in capturing the intricate spatial and temporal dependencies inherent in traffic flow. In response to these challenges, we present GRAPHITE, an innovative framework that combines Graph Neural Networks (GNNs) and Generative Adversarial Networks (GANs) to leverage generative reasoning for efficient traffic management. Our model seamlessly integrates historical traffic volume data collected by road sensors with local spatial information encoded through knowledge graphs (KGs) associated with each sensor. These KGs offer a structured representation of relationships between traffic sensors and points of interest (POIs) in their neighborhood, thereby enhancing the comprehension of the urban context and leading to more accurate traffic predictions. Extensive experiments conducted on diverse datasets underscore the efficacy of GRAPHITE. Notably, we achieved a maximum decrease in RMSE of 31.05% compared to GAN-GRU and a maximum increase in R2 of 8.15% compared to GAN-RNN, positioning GRAPHITE as a standout solution among the current state-of-the-art approaches. Our code is available at: https://github.com/MODAL-UNINA/GRAPHITE.

Evaluating the Safety of Microbial Enzyme Preparations Used in Food Processing: Update for a New Century

BackgroundComprehensively mapping the hierarchical structure of breast cancer protein communities and identifying potential biomarkers from them is a promising way for breast cancer research. Existing approaches are subjective and fail to take information from protein sequences into consideration. Deep learning can automatically learn features from protein sequences and protein–protein interactions for hierarchical clustering.ResultsUsing a large amount of publicly available proteomics data, we created a hierarchical tree for breast cancer protein communities using a novel hierarchical graph neural network, with the supervision of gene ontology terms and assistance of a pre-trained deep contextual language model. Then, a group-lasso algorithm was applied to identify protein communities that are under both mutation burden and survival burden, undergo significant alterations when targeted by specific drug molecules, and show cancer-dependent perturbations. The resulting hierarchical map of protein communities shows how gene-level mutations and survival information converge on protein communities at different scales. Internal validity of the model was established through the convergence on BRCA2 as a breast cancer hotspot. Further overlaps with breast cancer cell dependencies revealed SUPT6H and RAD21, along with their respective protein systems, HOST:37 and HOST:861, as potential biomarkers. Using gene-level perturbation data of the HOST:37 and HOST:861 gene sets, three FDA-approved drugs with high therapeutic value were selected as potential treatments to be further evaluated. These drugs include mercaptopurine, pioglitazone, and colchicine.ConclusionThe proposed graph neural network approach to analyzing breast cancer protein communities in a hierarchical structure provides a novel perspective on breast cancer prognosis and treatment. By targeting entire gene sets, we were able to evaluate the prognostic and therapeutic value of genes (or gene sets) at different levels, from gene-level to system-level biology. Cancer-specific gene dependencies provide additional context for pinpointing cancer-related systems and drug-induced alterations can highlight potential therapeutic targets. These identified protein communities, in conjunction with other protein communities under strong mutation and survival burdens, can potentially be used as clinical biomarkers for breast cancer.