Mass & secondary structure propensity of amino acids explain their mutability and evolutionary replacements

Why is an amino acid replacement in a protein accepted during evolution? The answer given by bioinformatics relies on the frequency of change of each amino acid by another one and the propensity of each to remain unchanged. We propose that these replacement rules are recoverable from the secondary structural trends of amino acids. A distance measure between high-resolution Ramachandran distributions reveals that structurally similar residues coincide with those found in substitution matrices such as BLOSUM: Asn Asp, Phe Tyr, Lys Arg, Gln Glu, Ile Val, Met → Leu; with Ala, Cys, His, Gly, Ser, Pro, and Thr, as structurally idiosyncratic residues. We also found a high average correlation (\overline{R} R = 0.85) between thirty amino acid mutability scales and the mutational inertia (I X ), which measures the energetic cost weighted by the number of observations at the most probable amino acid conformation. These results indicate that amino acid substitutions follow two optimally-efficient principles: (a) amino acids interchangeability privileges their secondary structural similarity, and (b) the amino acid mutability depends directly on its biosynthetic energy cost, and inversely with its frequency. These two principles are the underlying rules governing the observed amino acid substitutions. © 2017 The Author(s)

Deep Learning for Genomics: A Concise Overview

Advancements in genomic research such as high-throughput sequencing techniques have driven modern genomic studies into "big data" disciplines. This data explosion is constantly challenging conventional methods used in genomics. In parallel with the urgent demand for robust algorithms, deep learning has succeeded in a variety of fields such as vision, speech, and text processing. Yet genomics entails unique challenges to deep learning since we are expecting from deep learning a superhuman intelligence that explores beyond our knowledge to interpret the genome. A powerful deep learning model should rely on insightful utilization of task-specific knowledge. In this paper, we briefly discuss the strengths of different deep learning models from a genomic perspective so as to fit each particular task with a proper deep architecture, and remark on practical considerations of developing modern deep learning architectures for genomics. We also provide a concise review of deep learning applications in various aspects of genomic research, as well as pointing out potential opportunities and obstacles for future genomics applications.Comment: Invited chapter for Springer Book: Handbook of Deep Learning Application

BERTDom: Protein Domain Boundary Prediction Using BERT

The domains of a protein provide an insight on the functions that the protein can perform. Delineation of proteins using high-throughput experimental methods is difficult and a time-consuming task. Template-free and sequence-based computational methods that mainly rely on machine learning techniques can be used. However, some of the drawbacks of computational methods are low accuracy and their limitation in predicting different types of multi-domain proteins. Biological language modeling and deep learning techniques can be useful in such situations. In this study, we propose BERTDom for segmenting protein sequences. BERTDOM uses BERT for feature representation and stacked bi-directional long short term memory for classification. We pre-train BERT from scratch on a corpus of protein sequences obtained from UniProt knowledge base with reference clusters. For comparison, we also used two other deep learning architectures: LSTM and feed-forward neural networks. We also experimented with protein-to-vector (Pro2Vec) feature representation that uses word2vec to encode protein bio-words. For testing, three other bench-marked datasets were used. The experimental results on benchmarks datasets show that BERTDom produces the best F-score as compared to other template-based and template-free protein domain boundary prediction methods. Employing deep learning architectures can significantly improve domain boundary prediction. Furthermore, BERT used extensively in NLP for feature representation, has shown promising results when used for encoding bio-words. The code is available at https://github.com/maryam988/BERTDom-Code

Soft Computing Techiniques for the Protein Folding Problem on High Performance Computing Architectures

The protein-folding problem has been extensively studied during the last fifty years. The understanding of the dynamics of global shape of a protein and the influence on its biological function can help us to discover new and more effective drugs to deal with diseases of pharmacological relevance. Different computational approaches have been developed by different researchers in order to foresee the threedimensional arrangement of atoms of proteins from their sequences. However, the computational complexity of this problem makes mandatory the search for new models, novel algorithmic strategies and hardware platforms that provide solutions in a reasonable time frame. We present in this revision work the past and last tendencies regarding protein folding simulations from both perspectives; hardware and software. Of particular interest to us are both the use of inexact solutions to this computationally hard problem as well as which hardware platforms have been used for running this kind of Soft Computing techniques.This work is jointly supported by the FundaciónSéneca (Agencia Regional de Ciencia y Tecnología, Región de Murcia) under grants 15290/PI/2010 and 18946/JLI/13, by the Spanish MEC and European Commission FEDER under grant with reference TEC2012-37945-C02-02 and TIN2012-31345, by the Nils Coordinated Mobility under grant 012-ABEL-CM-2014A, in part financed by the European Regional Development Fund (ERDF). We also thank NVIDIA for hardware donation within UCAM GPU educational and research centers.Ingeniería, Industria y Construcció

Computational Design of Stable and Soluble Biocatalysts

Natural enzymes are delicate biomolecules possessing only marginal thermodynamic stability. Poorly stable, misfolded, and aggregated proteins lead to huge economic losses in the biotechnology and biopharmaceutical industries. Consequently, there is a need to design optimized protein sequences that maximize stability, solubility, and activity over a wide range of temperatures and pH values in buffers of different composition and in the presence of organic cosolvents. This has created great interest in using computational methods to enhance biocatalysts' robustness and solubility. Suitable methods include (i) energy calculations, (ii) machine learning, (iii) phylogenetic analyses, and (iv) combinations of these approaches. We have witnessed impressive progress in the design of stable enzymes over the last two decades, but predictions of protein solubility and expressibility are scarce. Stabilizing mutations can be predicted accurately using available force fields, and the number of sequences available for phylogenetic analyses is growing. In addition, complex computational workflows are being implemented in intuitive web tools, enhancing the quality of protein stability predictions. Conversely, solubility predictors are limited by the lack of robust and balanced experimental data, an inadequate understanding of fundamental principles of protein aggregation, and a dearth of structural information on folding intermediates. Here we summarize recent progress in the development of computational tools for predicting protein stability and solubility, critically assess their strengths and weaknesses, and identify apparent gaps in data and knowledge. We also present perspectives on the computational design of stable and soluble biocatalysts

Highly Accurate Fragment Library for Protein Fold Recognition

Proteins play a crucial role in living organisms as they perform many vital tasks in every living cell. Knowledge of protein folding has a deep impact on understanding the heterogeneity and molecular functions of proteins. Such information leads to crucial advances in drug design and disease understanding. Fold recognition is a key step in the protein structure discovery process, especially when traditional computational methods fail to yield convincing structural homologies. In this work, we present a new protein fold recognition approach using machine learning and data mining methodologies. First, we identify a protein structural fragment library (Frag-K) composed of a set of backbone fragments ranging from 4 to 20 residues as the structural “keywords” that can effectively distinguish between major protein folds. We firstly apply randomized spectral clustering and random forest algorithms to construct representative and sensitive protein fragment libraries from a large-scale of high-quality, non-homologous protein structures available in PDB. We analyze the impacts of clustering cut-offs on the performance of the fragment libraries. Then, the Frag-K fragments are employed as structural features to classify protein structures in major protein folds defined by SCOP (Structural Classification of Proteins). Our results show that a structural dictionary with ~400 4- to 20-residue Frag-K fragments is capable of classifying major SCOP folds with high accuracy. Then, based on Frag-k, we design a novel deep learning architecture, so-called DeepFrag-k, which identifies fold discriminative features to improve the accuracy of protein fold recognition. DeepFrag-k is composed of two stages: the first stage employs a multimodal Deep Belief Network (DBN) to predict the potential structural fragments given a sequence, represented as a fragment vector, and then the second stage uses a deep convolution neural network (CNN) to classify the fragment vectors into the corresponding folds. Our results show that DeepFrag-k yields 92.98% accuracy in predicting the top-100 most popular fragments, which can be used to generate discriminative fragment feature vectors to improve protein fold recognition

CoGANPPIS: Coevolution-enhanced Global Attention Neural Network for Protein-Protein Interaction Site Prediction

Protein-protein interactions are essential in biochemical processes. Accurate prediction of the protein-protein interaction sites (PPIs) deepens our understanding of biological mechanism and is crucial for new drug design. However, conventional experimental methods for PPIs prediction are costly and time-consuming so that many computational approaches, especially ML-based methods, have been developed recently. Although these approaches have achieved gratifying results, there are still two limitations: (1) Most models have excavated some useful input features, but failed to take coevolutionary features into account, which could provide clues for inter-residue relationships; (2) The attention-based models only allocate attention weights for neighboring residues, instead of doing it globally, neglecting that some residues being far away from the target residues might also matter. We propose a coevolution-enhanced global attention neural network, a sequence-based deep learning model for PPIs prediction, called CoGANPPIS. It utilizes three layers in parallel for feature extraction: (1) Local-level representation aggregation layer, which aggregates the neighboring residues' features; (2) Global-level representation learning layer, which employs a novel coevolution-enhanced global attention mechanism to allocate attention weights to all the residues on the same protein sequences; (3) Coevolutionary information learning layer, which applies CNN & pooling to coevolutionary information to obtain the coevolutionary profile representation. Then, the three outputs are concatenated and passed into several fully connected layers for the final prediction. Application on two benchmark datasets demonstrated a state-of-the-art performance of our model. The source code is publicly available at https://github.com/Slam1423/CoGANPPIS_source_code

Unveiling the frontiers of deep learning: innovations shaping diverse domains

Deep learning (DL) enables the development of computer models that are capable of learning, visualizing, optimizing, refining, and predicting data. In recent years, DL has been applied in a range of fields, including audio-visual data processing, agriculture, transportation prediction, natural language, biomedicine, disaster management, bioinformatics, drug design, genomics, face recognition, and ecology. To explore the current state of deep learning, it is necessary to investigate the latest developments and applications of deep learning in these disciplines. However, the literature is lacking in exploring the applications of deep learning in all potential sectors. This paper thus extensively investigates the potential applications of deep learning across all major fields of study as well as the associated benefits and challenges. As evidenced in the literature, DL exhibits accuracy in prediction and analysis, makes it a powerful computational tool, and has the ability to articulate itself and optimize, making it effective in processing data with no prior training. Given its independence from training data, deep learning necessitates massive amounts of data for effective analysis and processing, much like data volume. To handle the challenge of compiling huge amounts of medical, scientific, healthcare, and environmental data for use in deep learning, gated architectures like LSTMs and GRUs can be utilized. For multimodal learning, shared neurons in the neural network for all activities and specialized neurons for particular tasks are necessary.Comment: 64 pages, 3 figures, 3 table

DeepFrag-k: A Fragment-Based Deep Learning Approach for Protein Fold Recognition

Background: One of the most essential problems in structural bioinformatics is protein fold recognition. In this paper, we design a novel deep learning architecture, so-called DeepFrag-k, which identifies fold discriminative features at fragment level to improve the accuracy of protein fold recognition. DeepFrag-k is composed of two stages: the first stage employs a multi-modal Deep Belief Network (DBN) to predict the potential structural fragments given a sequence, represented as a fragment vector, and then the second stage uses a deep convolutional neural network (CNN) to classify the fragment vector into the corresponding fold. Results: Our results show that DeepFrag-k yields 92.98% accuracy in predicting the top-100 most popular fragments, which can be used to generate discriminative fragment feature vectors to improve protein fold recognition. Conclusions: There is a set of fragments that can serve as structural “keywords” distinguishing between major protein folds. The deep learning architecture in DeepFrag-k is able to accurately identify these fragments as structure features to improve protein fold recognition