Protein Science Meets Artificial Intelligence: A Systematic Review and a Biochemical Meta-Analysis of an Inter-Field

Abstract

Proteins are some of the most fascinating and challenging molecules in the universe, and they pose a big challenge for artificial intelligence. The implementation of machine learning/AI in protein science gives rise to a world of knowledge adventures in the workhorse of the cell and proteome homeostasis, which are essential for making life possible. This opens up epistemic horizons thanks to a coupling of human tacit–explicit knowledge with machine learning power, the benefits of which are already tangible, such as important advances in protein structure prediction. Moreover, the driving force behind the protein processes of self-organization, adjustment, and fitness requires a space corresponding to gigabytes of life data in its order of magnitude. There are many tasks such as novel protein design, protein folding pathways, and synthetic metabolic routes, as well as protein-aggregation mechanisms, pathogenesis of protein misfolding and disease, and proteostasis networks that are currently unexplored or unrevealed. In this systematic review and biochemical meta-analysis, we aim to contribute to bridging the gap between what we call binomial artificial intelligence (AI) and protein science (PS), a growing research enterprise with exciting and promising biotechnological and biomedical applications. We undertake our task by exploring “the state of the art” in AI and machine learning (ML) applications to protein science in the scientific literature to address some critical research questions in this domain, including What kind of tasks are already explored by ML approaches to protein sciences? What are the most common ML algorithms and databases used? What is the situational diagnostic of the AI–PS inter-field? What do ML processing steps have in common? We also formulate novel questions such as Is it possible to discover what the rules of protein evolution are with the binomial AI–PS? How do protein folding pathways evolve? What are the rules that dictate the folds? What are the minimal nuclear protein structures? How do protein aggregates form and why do they exhibit different toxicities? What are the structural properties of amyloid proteins? How can we design an effective proteostasis network to deal with misfolded proteins? We are a cross-functional group of scientists from several academic disciplines, and we have conducted the systematic review using a variant of the PICO and PRISMA approaches. The search was carried out in four databases (PubMed, Bireme, OVID, and EBSCO Web of Science), resulting in 144 research articles. After three rounds of quality screening, 93 articles were finally selected for further analysis. A summary of our findings is as follows: regarding AI applications, there are mainly four types: 1) genomics, 2) protein structure and function, 3) protein design and evolution, and 4) drug design. In terms of the ML algorithms and databases used, supervised learning was the most common approach (85%). As for the databases used for the ML models, PDB and UniprotKB/Swissprot were the most common ones (21 and 8%, respectively). Moreover, we identified that approximately 63% of the articles organized their results into three steps, which we labeled pre-process, process, and post-process. A few studies combined data from several databases or created their own databases after the pre-process. Our main finding is that, as of today, there are no research road maps serving as guides to address gaps in our knowledge of the AI–PS binomial. All research efforts to collect, integrate multidimensional data features, and then analyze and validate them are, so far, uncoordinated and scattered throughout the scientific literature without a clear epistemic goal or connection between the studies. Therefore, our main contribution to the scientific literature is to offer a road map to help solve problems in drug design, protein structures, design, and function prediction while also presenting the “state of the art” on research in the AI–PS binomial until February 2021. Thus, we pave the way toward future advances in the synthetic redesign of novel proteins and protein networks and artificial metabolic pathways, learning lessons from nature for the welfare of humankind. Many of the novel proteins and metabolic pathways are currently non-existent in nature, nor are they used in the chemical industry or biomedical field.

Introduction

Protein science witnesses the most exciting and demanding revolution of its own field; the magnitude of its genetic–epigenetic—molecular networks, inhibitors, activators, modulators, and metabolite information—is astronomical. It is organized in an open “protein self-organize, adjustment and fitness space”; for example, a protein of 100 amino acids would contain 20¹⁰⁰ variants, and a process of searching–finding conformations in a protein of 100 amino acids can adopt ∼10⁴⁶ conformation and a unique native state, the protein data exceeding many petabytes (1 petabyte is 1 million gigabytes) (Kauffman, 1992).

Therefore, the use of artificial intelligence in protein science is creating new avenues for understanding the ways of organizing and classifying life within its organisms to eventually design, control, and improve this organization. In this respect, protein synthesis is a case in point. Indeed, the discovery of the underlying mechanism of protein synthesis is an inter-field discovery, that is, “a significant achievement of 20th century biology that integrated results from two fields: molecular biology and biochemistry” (Baetu, 2015). More recently, the field of protein science is, in turn, another inter-field enterprise, this time between molecular biology and computer science, or better said, between a cross-functional team of researchers (biochemists, protein scientists, protein engineers, system biology scientists, bioinformatics, between others). Nowadays, it is possible to classify, share, and use a significant number of structural biology databases helping researchers throughout the world. Once the mechanism of DNA for protein synthesis is deduced, it will then be possible to replicate it via computational strategies through artificial intelligence (AI) and machine learning (ML) algorithms that can provide important information such as pattern recognition, nearest neighbors, vector profiles, back propagation, among others. AI has been used to exploit this novel knowledge to predict, design, classify, and evolve known proteins with improved and enhanced properties and applications in protein science (Paladino et al., 2017; Wardah et al., 2019;Cheng et al., 2008; Bernardes and Pedreira, 2013), which, in turn, makes its way to solve complex problems in the “fourth industrial revolution” and open new areas of protein research, growing at a very fast speed.

The techniques of machine learning are a subfield of AI, which has become popular due to the linear and non-linear processed data and the large amount of available combinatorial spaces. As a result, sophisticated algorithms have emerged, promoting the use of neural networks (Gainza et al., 2016) However, in spite of the large amount of research done in protein science, as far as we know, there are neither systematic reviews nor any biochemical meta-analysis in the scientific literature informing, illuminating, and guiding researchers on the best available ML techniques for particular tasks in protein science; albeit there have been recent reviews such as the work of AlQuraishi (2021), Dara et al. (2021), and Hie and Yang (2022), which prove that this inter-field is on evolution. By a biochemical meta-analysis, we mean an analysis resulting from two processes: identification and prediction. The former consists of identifying AI applications into the protein field where we classify and identify active and allosteric sites, molecular signatures, and molecular scaffolding not yet described in nature.

Each structural signature, pattern, or profile constitutes a singular part of the whole “lego-structure-kit” that is the protein space that includes the catalytic task space and shape space, which Kauffman (1992) defines as an abstract representation or mapping of all shapes and chemical reactions that can be catalyzed onto a space of task. The latter process is an analysis of the resulting predictions of structures, molecular signatures, regulatory sites, and ligand sites. Both processes are related to each other in the sense that the proteins in the identification process are searching targets of the 3D-structure for the prediction process that predicts the protein conformation multiple times from a template family or using model-free approach. The biochemical meta-analysis includes formulating the research question, searching and classifying protein tasks in the selected studies, gathering AI–PS information from the studies, evaluating the quality of the studies, analyzing and classifying the outcomes of studies, building up tables and figures for the interpretation of evidence, and presenting the results.

This study puts forward the use of ML classes and methods to address complex problems in protein science. Our point of departure is the state of the art of the AI–PS binomial; by binomial, we mean a biological name consisting of two terms that are partners in computational science as well as in biomedical or biotechnological science as a “two-feet principle” in order to understand, enhance, and control protein science development from an artificial intelligence perspective. Our cross-functional team aims at accelerating the steps of translating the basic scientific knowledge from protein science laboratories into AI applications. Here, we report a comprehensive, balanced systematic review for the literature in the inter-field and a biochemical meta-analysis, which includes a classification of screened articles: 1) by the ML techniques, they use and narrowing down the subareas, 2) by the classes, methods, algorithms, prediction type and programming language, 3) by some protein science queries, 4) by protein science applications, and 5) by protein science problems. Moreover, we present the main contributions of AI in several tasks, as well as a general outline of the processes that are carried out throughout the construction of the models and their applications. We outline a discussion on the best practices of validation, cross-validation, and individual control of testing ML models in order to assess the role that they play in the progress of ML techniques, integrating several data types and developing novel interpretations of computational methodology, thus enabling a wider range of protein’s-universe impacts. Finally, we provide future direction for machine learning approaches in the design of novel proteins, metabolic pathways, and synthetic redesign of protein networks.

Materials and Methods

A systematic review of the scientific literature found in the period (until February 2021) was carried out for this study (Figures 1–3) following the PIO (participants/intervention/outcome) approach and according to PRISMA declaration (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Supplementary. No ethical approval or letter of individual consent was required for this research.

FIGURE 1

FIGURE 2

FIGURE 3

PIO Strategy

One of the main objectives is to discuss new information in the latest findings about the functions of AI in protein design. Furthermore, this review and meta-analysis intend to include a wide scope of the status of artificial intelligence in protein science. The PIO (participants, intervention, and outcome) strategy was used to systematically search all databases and was the methodology to address the following research questions: What is the state of art in the use of artificial intelligence in the protein science field? What is the use of neural networks in the rational design of proteins? Which neural networks are used in the rational design of proteins? Protein design is currently considered a challenge. As artificial intelligence makes progress, this is presented as a solution to various issues toward addressing how this new branch can be used for the creation of high precision models in protein design. Following the PIO strategy, the next terms were used for the research.

Intervention: studies with any types of algorithms, software, programming language, platform, or paradigm using alone or in combination were selected.

Databases and Searches

The electronic databases used were PubMed, Bireme, EBSCO, and OVID. The concepts with similarity were searched with “OR,” and within the groups of each element of the PIO research, they were searched with the word “AND.” Next, a diagram was constructed in order to show the history of searches and concepts used (figure tree diagram). This figure describes in full detail the searching strategy in the PubMed database as well as all keywords used. Moreover, it includes the number of resulting articles. Subsequently, the results obtained from these searches were recorded. The references themselves were then downloaded into the Mendeley database. All references were taken, organized, and saved in Mendeley, eliminating duplicates for the final result.

Biochemical Meta-analysis

The biochemical meta-analysis included formulating the research question, searching and classifying protein tasks in the 144 selected studies, gathering AI–PS information from the 144 studies, evaluating the quality of the studies (as described in the systematic review, see flowchart of PRISMA), analyzing and classifying the intervention and outcome of studies (networks, software, programming languages, development platforms, paradigms, novel proteins, novel scaffold, new fold, etc.), and building up tables and figures for the interpretation of evidence and presenting the results.

By a biochemical meta-analysis, we mean an analysis resulting from two processes: identification and prediction. The former consists of identifying AI applications into the protein field: classify and identify active and allosteric sites, molecular signatures, and molecular scaffolding not yet described in nature, each of which constitute a single part of a grand-type Lego structure. The latter is an analysis of resulting predictions: structures, molecular signatures, regulatory and ligand sites, etc.

Biochemical Meta-Analysis and Designing the Road Map

PRELIMINARY: we determined the formulation of the problem and objectives of the research within the figure, which includes the treatment of the data and their applications. Note: the information was acquired from a list of various databases from which data were analyzed.

DATA COLLECTION: primary data: observation, research and review of articles. Secondary data: data of the reviewed articles and information shared among keywords.

DATA PRE-PROCESSING (ETL and training): identification of filtered data, curated data, and features implemented; machine learning input relationship with protein science servers.

DATA PROCESSING (training data and feature extraction): observation of input data and data encoding format. Record of machine learning algorithms and methods. Recognition of key information for processing data within databases.

DATA POST-PROCESSING: observation of post-processing treatment, rule quality processing, filtering, combination, or unification of information.

MEASURE: explanation of the process, the values of different metrics for the quantification of magnitudes, and the contribution for the completion within the process of information.

ANALYZE: identify the application of machine learning algorithm in which the input of the dataset to process data format, training set, and 3D structures.

IMPROVE: determine the set to whom these new forms will be applied in models of the researched data and contribute to future implementations in protein science.

Concerning the computational aspects as to how articles were classified, three initial divisions were made and are displayed in Table 1: Pre-process, process, and post-process, each of which contain, in turn, the following items:

pre-process

database, pretreatment, and input

process

machine learning paradigm and input, algorithm and development software, three aspects of the neural network used (characteristics, strengths, and limitations) and output.

post-process

input and web server when applied.

Most of the research reported in these articles performs a pretreatment over the protein database used, that is, processes of randomization and training, in order to leave the data prepared for the computational process itself, for when the algorithm is to be executed on a software platform and within a particular machine learning paradigm (mostly supervised, unsupervised, and deep learning, as shown in Figure 4). We also reported special characteristics as well as strengths and limitations of the neural networks used. Finally, part of the post-process, when applied, concerns the web server where research results are stored. Moreover, some of these aspects are also registered in Tables 2–6 as well as some others (programming language and software license type).

FIGURE 4

Results

Article Scaffolding

This article is arranged as follows (Figure 2): first, we provide a representation of the process in designing, preparing, and describing of the guideline throughout the article. Secondly, we review the presented formulation of the research question toward the determined problem formulation and objectives of the research, including the treatment of the data and the applications of it. Thirdly, the article processes the observation, research, and review of a series of articles to further study the data obtained and review similarities. Furthermore, the gathering of AI–PS information, within this processing of the identification of filtered data, curated data and features implemented, the observation of input data, data encoding format, recording of machine learning algorithms and methods, as so the post-processing treatment, quality rule processing, filtering, combination, or unification of information, which passes into the interpretation of the information recollected, and representation of it by the usage of figures and tables, portrays the results, which are focused on the latest findings of AI applications in the field of protein science as well as the usage of specific algorithms for protein design. Therefore, this aims to include a wide-scope range of the state of the art of artificial intelligence within protein science; this leads us to a latter analysis and discussion regarding the identification and prediction of AI applications into the protein field, by classification and identification of main protein structures, and other components not found or described yet in nature, and the resolution of possible protein prediction structures and other components of them are plausible outcomes of future research.

Toward an Innovative Cross-Functional AI–PS Binomial Inter-field

This systematic review and meta-analysis are focused on the latest findings of AI applications to the field of protein science as well as specific algorithms used for protein design. Furthermore, it aims to include a wide scope of the state of the art of artificial intelligence in protein science. PIO is the methodology used to address the following research question: What is the state of the art in the use of artificial intelligence in the protein science field? Figure 1 shows the total number of articles retrieved using the PIO strategy in the PubMed database.

The systematic review process began with 541 references obtained from five electronic databases: 42 were from PubMed, 74 were from Ebsco, 48 were from Bireme, 38 were from OVID, and 339 were from Web of Science. In the first screening, 403 articles were removed: 250 articles with a double reference; 2 not written in Spanish or English; 149 whose topic was irrelevant to the review; and two newspapers, letters, or reviews. This election process left 138 references, and manually we added 6, thus getting a total of 144 articles for the review (Figure 3).

A total of 93 articles were included for further analysis, and 51 studies were removed based on quality criteria.

Machine Learning Approach to Protein Science

Proteins are influenced by epigenetic phenomena (cellular stress, aging, etc.) because of their multiple structure-folding-function within protein science (PS), phenomena that can be challenged through the use of artificial intelligence (AI).There are several questions within this interdisciplinary approach such as How do proteins evolve? How do proteins fold and get their tridimensional structure? What are their networks within proteins? Given the astronomical numbers of possibilities for protein structures, configurations, and functions that require the use of AI as a tool to fully understand protein behavior.

FIGURE 5

FIGURE 6

From the studies reviewed, (23/144), 16% use two databases. Of these, the latter (11/23) 48% uses a combination of the PDB and HSPP, PISCES, ProTherm, MOAD, SPx dataset, ChEMBL, DisProt, and UniProt/SwissProt; (4/23)17% use a combination of the GO database with UniProt or STRING; (4/23)17% uses a combination of the UniProt/SwissProt database with ENZYME, DIP, TrEMBL, and CAFA database; and a (2/23)9% combination among DIP, HPRD, SKEMPI database, and SPx dataset. The rest (24/144)17% belongs to a combination of three or more databases with PDB, UniProt, among others.

Moreover, several authors (Shamim et al., 2007; Simha et al., 2015; Yang et al., 2015; Li et al., 2018; Torng and Altman, 2019) focused on using previously constructed datasets, while others chose the creation of their own, based on their own design and outcome, for example, NOS, PPI’s, SPX, DBMLoc, D-B, and Extended D-B (Tables 2–6 and Figure 5).

The following tables show the principal protein categories that were found in this study. Table 2 shows the result of each of the 38 articles that were considered in the protein and drug design category.

Table 3 shows 26 studies that are related to protein function prediction and 6 studies related to function prediction and novel function.

Table 4 shows 19 studies that are related to fold ID and physicochemical properties and 8 studies related to protein classification.

Table 5 shows 26 studies that are related to protein structure prediction.

Table 6 shows five studies for protein contact map prediction, five studies for protein-binding prediction, nine studies for protein site prediction, and two studies for genomics.

Table 1 shows the overview of the extracted information of the selected studies based on the quality criteria.

Machine Learning Paradigms and AI Algorithm Roles

The most applied approach we found as a result of our review and meta-analysis corresponds to supervised learning (123/144)85%, which focuses on classification algorithms (CNN, NB, KNN, RF, SVM, etc.) and regression algorithms (SVR, RFR, DT, ANN, DNN, etc.) that are used for a variety of tasks: detection of functional sites, hydroxylation sites, amino acid composition, DNA expression sequences, protein interaction, biomarker finding, protein design, drug design, 3D structure prediction, and protein folding (Tables 2–6 and Figures 4, 5). Within supervised machine learning (123), we found that classification techniques overrule, by far, regression ones (31/123) (for reference, seeTables 2–6). On a closer look, we see that these methods are generally very good at prediction tasks, although complexity may be significantly increased by the execution time required, something that is often reported as a drawback of this method (AlQuraishi, 2021).

In contrast to supervised learning, it is only (17/144)12% focusing on unsupervised learning, using clustering algorithms (CNN, FFNN, LSDR, DL, HMM, MRF, NN, etc.) for various purposes, such as protein solubility prediction, protein prediction of new functions, discovery of DNA motifs, detection of protein structures, and prediction of the nuclear Overhauser effect at low energies. Of the eight articles using this approach, two of them report an improvement in performance as an advantage, one of them in time reduction (Frasca et al., 2018) and the other one in the acceleration of automated protein function prediction methods in general (Makrodimitris et al., 2019). At the same time, however, a disadvantage reported is that time execution may be increased, a fact that should not surprise us, for it is well known that unsupervised learning algorithms are characterized by being computationally very complex methods (Table 1 and Figures 4–7).

On the other hand, supervised machine learning is used just a little more than deep learning techniques. Moreover, it is interesting to note that roughly (77/144)53% of the deep learning articles combine two clustering algorithms: CNN (47/77)61% and LSTM (16/77)21%. Of course, some articles put forward optimization procedures in an algorithmic genetic fashion (Figures 4–7).

Regarding hybrid algorithms using neural networks, we found that all 11 articles explicitly stating their use of hybrid algorithms belong to the deep learning paradigm, combining CNN and LSTM or RNN and CNN. One of them (Almagro Armenteros et al., 2017) goes even further; in that, it uses a combination of these two neural networks to predict protein subcellular localization and then an attention mechanism to identify protein regions important for subcellular localization (Table 1 and Figures 4–6).

It is interesting to note as well that nine articles are used for prediction (glycation product prediction (Chen et al., 2019), protein secondary structure (Guo et al., 2019), prediction of metal binding in proteins (Haberal and Ogul, 2019), compound–protein affinity prediction (Karimi et al., 2019), prediction of protein structural features (Klausen et al., 2019), protein contact map prediction (Hanson et al., 2018), prediction of protein interactions (Huang et al., 2018), predicting hydroxylation sites (Long et al., 2018), and predicting protein subcellular localization (Almagro Armenteros et al., 2017)), of which two perform prediction from original sequences (Almagro Armenteros et al., 2017;Li et al., 2018).

Moreover, one of them highlights that one of its applications is for the design of new drugs and one of them performs this task (Karimi et al., 2019).

It is tempting to put forward the claim that hybrid algorithms in deep learning are very good for prediction tasks as well as for applications in the new drug design. It is noteworthy to mention that these articles belong to the last 3 years of our revision, something that suggests that there is a tendency for the use of hybrid methods in the near future (Table 1).

AI Training, Validation, and Performance

Validation process allows obtaining a quantitative measure of the models’ efficiency. In this systematic review, several methodologies were used to train and validate in the machine and deep learning proposed by means of hold-out and k-fold cross-validation; The most utilized was the k-fold cross-validation, each one with a different folding proposal, e.g., 2-, 3-, 5-, and 10-fold (Szalkai and Grolmusz, 2018a), trained and validated its algorithm utilizing two validations: 3- and 5-fold cross-validations. Several articles used a graphics processing unit (GPU) that was employed to accelerate the deep learning training and validation process. The most utilized AI algorithm in these articles was CNN, with a 33% occurrence, followed by DNN with 9%, both programmed with Python. The performance of the AI algorithms for protein design was evaluated using parameters such as sensitivity, specificity, true-positive rate, false-positive rate, accuracy, recall, precision, F1-score, area under the curve (AUC), receiver operating characteristic (ROC) curve, and Matthew’s correlation coefficient (MCC). For the case of the hold-out validation, a percentage of the data that is taken and that percentage is randomly removed from the dataset is selected. This methodology, in particular, is computationally very simple; however, it suffers from a high variance because it is not known that data will end up in the test set or in the training one and of the importance that these data might have. In hold-out validation, datasets, which for this review are the databases of proteins, genes, peptides, etc. (seeTables 2–6 and Figures 4–6), are randomly divided into two partitions with different proportions (50, 70, or 75% training—50, 30, or 25% validation), which are mutually exclusive. The first part of the database is used to feed the input vectors of the methods and train the machine or deep learning algorithms, while the rest is used to evaluate and validate the results obtained with their proposed algorithms. In contrast, with this type of validation technique, hold-out takes a long time for computational processing, especially for large datasets, in particular case, the large protein databases. As a result of our meta-analysis, we found the use of the hold-out methodology to train and validate their AI proposals, as CNN, RNN, LSTM, and FFNN (Tables 1–6 and Figures 4–6) in the prediction of expressions, interactions, and subcellular localization of proteins and also in the prediction of the peptide binding.

Another technique for evaluating the performance of AI methods, particularly for large databases such as protein design, is cross-validation. Cross-validation is a technique used to (generally) obtain the ability of a model to fit an unknown dataset given a collected dataset. In this context, the k-fold cross-validation is an iterative process that consists of dividing the dataset randomly into k groups of approximately the same size. In this sense, although not all possible combinations of sets are examined, an estimate of the average accuracy more than acceptable can be obtained by training the model only k-fold. The first set is used to train the AI models and the other is used to test and validate them, doing this process k times using a different group for validation in the iteration. Although cross-validation is computationally an intensive method of training and validation, its advantages are the reduction of computational time because the process is repeated k times, where all the data are tested once and used for training, maintaining a reduced variance and bias. Of the total 93 articles in this review, 41 of them (47%) used the following cross-validation schemes: leave-one-out, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 10-fold, and 20-fold cross-validations. For most of them, the use of 5-fold and 10-fold cross-validations to analyze the performance of their AI proposals predominated, with 16 and 17 articles, respectively. This method was preferred for the evaluation to the performance of CNN and SVM algorithms, with databases such as PBD, ProTherm, UniProt, GO, and ChEMBL. Additionally, in seven articles (17%), they carried out various types of cross-validations to obtain more information on the performance of their proposals. Another variant to evaluate performance was observed in three articles (7%), which combined the use of both hold-out and cross-validation methodologies in their proposals, which provide them more effective comparison of results in terms of validation schemes.

In contrast, in 22 articles of this review, 25% did not mention neither their training methods nor the validation performed to evaluate the performance of their algorithms used. Likewise, 7% of the articles evaluated their methods using various types of cross-validations at the same time to obtain more information on the performance of their proposals, e.g., 4-fold, 6-fold, 8-fold, and 1-fold, or 3-fold, 5-fold, 7-fold, and 1-fold, or 10- and 20-fold, for databases of PDB, UniProt, GO, ChEMBL, ProTherm, PISCES, GenBank, STRING, and new databases as NOS, SPx, D-B, and Ext D-B.

In general, the performance of all proposed AI algorithms was evaluated using several parameters such as sensitivity, specificity, true-positive rate, false-positive rate, accuracy, recall, precision, root-mean-square error (RMSE), R², F1-score, area under the curve (AUC), receiver operating characteristic (ROC) curve, and Matthew’s correlation coefficient (MCC) (Table 1).

Of the 87 articles selected as finalists, we have the following: 32 use one single algorithm and 55 use a combination of two or three algorithms sequentially. In machine learning, we found 30; in deep learning, we found 20 applying machine learning (SVM); 11 deep learning (RNN); and 6 using optimization through genetic algorithms.

Regarding the programming language in which each study was developed, we found 47 articles do not specify what language they are based on, 75 articles are based on the Python language, of which 57 are based entirely on Python and 18 are in combination with other software; seeTables 2–6.

Twelve articles are based on the C++ language of which only three are based exclusively on that language and nine in combination with Python, with C, R, and CUDA and C++ language in the Linux environment.

Other nine articles are based on MATLAB of which only four are based exclusively on that language and five in combination in conjunction with Python and Bioinformatics and with Python and C++.

Six articles are based on the C language of which three are based exclusively on that language and three in combination in conjunction with C++, R, and CUDA, with Java and Python and one with Linux and Windows environment.

Finally, seven articles are based on the Java language of which two are written exclusively in this language and five in combination with TensorFlow and with C and Python.

Regarding software licenses, 90 articles were found to be Open Source. An article is licensed by Neural Power version 2.5. One article specifies an open license type belonging to IBM and GNU, respectively. Unfortunately, 45 items did not specify the type of license they own.

Road Map of Artificial Intelligence in Protein Science

The goal of this analysis is to provide a road map to apply machine learning and AI techniques in protein science. One of the results of our meta-analysis, for example, in protein structure prediction, is shown in Figure 6 in which we can observe the two main strategies for protein structure prediction. In Figure 2, we show the scaffold-template-based modeling that is the most commonly used for the scientist in this field with very good results. However, recently Senior and collaborators using a free modeling approach successfully developed an AlphaFold algorithm using a deep neural network. They generated an outstanding accuracy of the 3D structure of a protein with an unknown fold in CASP14 (Senior et al., 2020). This led to an unsolved big question about the importance of the starting point in protein structure prediction, in particular, and in protein science, in general.

The road map of this research is an evolving and a dynamic process (Figure 7). It begins by obtaining information from a list of several databases, followed by a pre-treatment step over the extracted data, including those steps for eliminating redundancies within sequences, structure threshold based on RMSD values, and the like. Further steps contribute to the required pre-processing to complete the reporting process, and then proceed to the data process of the information itself, which includes the input data and the application of the machine learning algorithm, in which the input data are set to be processed into FASTA sequences, training sets, or 3D structures, depending on the function of algorithm in turn. The algorithms used fall into four categories: supervised learning, unsupervised learning, deep learning, and optimization, where each of these categories include a set of their own subparts, which are then combined and configured to predict new ways to model previous data and contribute to future implementations in protein science. The post-processing of data and the support of the new data acquired are made up of models and sequences that were loaded on the platforms to servers such as “DeepUbi, DeepSol, COSNet, Gnina, among others”, in which these servers are used for the storage or implementation of their respective methods. Figure 7 shows that more than half of the reported research completed the three pre-process, process and post-process steps we set forward, so this sequence may be applied to protein science including protein design, classification, physicochemical properties, functionalities, folding properties, and new functions such as homology prediction, domain prediction, subcellular localization, drug design, sensitivity, and other enhancers that can provide new catalysts and new functions, all of which provide any future development for biomolecular enhancement within protein science through machine learning. Model development is intrinsically related to the protein application to be developed. Data extraction varies depending on the architecture of the model to be developed since the data become more complex as the transformation, training, and feature extraction process unfold. The extraction ranges from obtaining the amino acid sequence, secondary structure to the 3D atomic model, using the atomic coordinates. Transforming data emphasizes on performing an adequate filtering for the use of the information for the training of the model, which leads to the feature extraction for the use of machine learning model and finally generating a final output. The process road map includes the fusion of these different applied AI learnings, models, and classifications into a connected deep learning layer that will be included in future research and test datasets to cover the terms of AI science, proteins, and their applications.

FIGURE 7

Final Discussion and Further Challenges for Our Understanding of Protein Science Using AI

Novelties and Future Direction in the Binomial PS-IA Research

The protein science field has great expectations on ML methods as indispensable tools for the biomedical sciences as well as for the chemical and biotechnology industry, for applied research is moving toward synthetic organisms with artificial metabolic networks, regulators, and so on, creating synthetic molecular factories. The binomial PS-IA research is evolving and strengthening, as shown in the Results section (Tables 1–6 and Figures 4–7). Our research reveals that road maps are most needed to solve complex problems in PS, guiding the exploration into the protein universe. As depicted in Table 1, ML techniques, which are used nowadays, are tailored to the expected results; Tables 1–6 display an array of networks of several solving problem methods, hence showing that guidance is needed in the form of road maps.

It is important to emphasize that in order to design a model algorithm bank functioning as a kit-tool, it is essential to understand the source from which the data are obtained and then used to train each model. The studies analyzed solve classification, regression, and optimization problems. As depicted in Table 1, models providing a solution make use of probabilistic inference, functions, activation functions, reduction of the hierarchical order, and logical inference. These results support the fact that machine learning models are heterogeneous, time demanding to design, and correctly evaluate complex models—since the result may not always be as expected or the method may not be carried out successfully. As illustrated in Table 3, there are some physical limitations blocking the full execution of the various models or algorithms, for example, when there is no appropriate computational equipment. Not surprisingly, several authors report that executing a model requires a high demand on execution time, computational power, extensive time to correctly evaluate the model, large memory consumption, and optimization toward GPUs (Frasca et al., 2018; Almagro Armenteros et al., 2017; Yeh et al., 2018; Jiménez et al., 2017; Lin et al., 2010). Another crucial aspect mentioned in Table 1 is the lack of input data to train the model, something that influences the model’s precision and accuracy (Pagès et al., 2019; Cuperus et al., 2017; Folkman et al., 2014; Qi et al., 2012). Moreover, there are also limitations in model construction, such as errors in the training process, manual intervention of data, overadjustment of the model, and an inadequate algorithm construction. In the studies analyzed, there are cases in which there is no description regarding the performance of the comprehensive models, generating gaps in the understanding of the behavior of the algorithms or models, like whether they are deterministic (Long et al., 2018; Ragoza et al., 2017; Makrodimitris et al., 2019). As stated in the ML and AI Algorithm section, supervised learning is the most used method, something that highlights the use of classification algorithms. Moreover, there seems to be a current trend to solve problems in protein science using techniques that require a cross-functional group of scientists, something that, in turn, highlights the fact that there is plenty of unexplored terrain in the use of unsupervised machine learning.

An interesting finding is the implementation of free code and software, as shown in the AI Training, Validation, and Performance section. Our results exhibit a tendency to create models with transparency, which means that every study implemented in a public server has access to all new models created. Another crucial result is the one depicted in the Road Map of Artificial Intelligence in Protein Science section, which is an abstraction that reduces the design of an artificial intelligence model to be used in the resolution of a specific problem in protein science. The whole process follows three steps directed to build a competent model; these steps are 1) the procedure to obtain raw data and which type of processing should be followed for the model to be adequate, 2) the type of algorithm that may be used depending on the complexity of the problem, and finally, 3) the interpretation of results.

Overall, AI displays a window of opportunities to solve complex problems in PS because of its potential in finding patterns and correlating information that requires the integration of protein data exceeding many petabytes. However, we are still far away from solving all the protein tasks computationally. As a result of our biochemical meta-analysis, we showed that AI applications are strongly directed to function identification and protein classification (Tables 1–6), for machine learning models and methods are heterogeneous and do not always draw a clear line as to whether a process should go in a certain sequence (Table 1 and Figures 4–7). It should also be noted that there is no optimal method, which is why applications have different purposes and conditions, suggesting that algorithms must be customized based on the expected outcome or query (Table 1).

The evaluation accuracy horizon is an open epistemic horizon, as shown in Table 1: the metrics for ML methods used in several applications are limited; there are no reported research articles using random forest, in which the cross-validation is unnecessary. In summary, none of the studies reported explicitly use robustly validated methods.

We end by commenting on a key problem in the binomial AI–PS. As well known, it is not possible to work directly with the protein sequences. To tackle this challenge, several studies address this limitation by representing the sequence of a protein as an input to the deep learning model (Almagro Armenteros et al., 2017; Long et al., 2018; Fu et al., 2019). Moreover, given some featured procedures comprising what may be called the coding architecture, which is based on creating a specific-weight matrix or a bit vector that represents the sample. This practice was observed in some articles (Cuperus et al., 2017; Jiménez et al., 2017; Khurana et al., 2018; Le et al., 2018) that work with 2D convolutional neural networks in which the authors reported an increase in sensitivity and precision when using indexed datasets. A similar abstraction was observed in 3D convolutional neural networks since the structural representation of a protein is not a rotational invariant; several authors (Jiménez et al., 2017; Ragoza et al., 2017; Hochuli et al., 2018; Pagès et al., 2019; Sunseri et al., 2019; Torng and Altman, 2019) propose using a volumetric map divided into voxels centered on the backbone atoms, representing the physicochemical properties of proteins.

Regarding other review articles along the lines we have followed, the closest we found is the one by Dara et al. (2021). This review article is restricted to drug discovery, one of the five applications we analyzed (genomics, protein structure and function, protein design and evolution, and drug design).

Of a total of 38 articles we presented in Table 2 concerning protein and drug design, only 11 of them were about protein design, so the comparison is not at all fair between these two articles, as far as the analysis of the bibliography analyzed is concerned. However, we share with these authors part of the challenges for researchers in this area: data quality as well as the heterogeneity of databases to be searched for.

Optimization and the characteristics of a prediction must be carried out with a few design considerations, including how to represent the protein data and what type of learning algorithm to use. These form the establishment of a priority acquisition, standard acquisition, etc., and the generation of a protein based on a base model, with the aim that one day it would be possible to have controllable predictive models that can read and generate outputs in a consensual terminology, as revised in Hie and Yang (2022). Clearly showing a replacement of conventional methods to the use of machine learning algorithms (neural networks), attributed to improvements in design, computational power, etc., the result of a machine learning algorithm is not deterministic, but rather, it is intended to perform transformation functions in relation to the complexity of the data, as depicted in AlQuraishi (2021). There are volumes and volumes of empirical protein data. It is extremely difficult to synthesize such data for correct use in existing algorithms; however, machine learning has helped to compile a large number of methodologies, considering specific assumptions. Nevertheless, most of the empirical methodologies to demonstrate that drugs are safe and effectively continue to be used since there is a gap in the understanding of how the learning transmission of the data to the model is carried out (Dara et al., 2021).

In order to close our reflection as a research team, we believe that a landmark for the epistemic horizon in research is the reassurance that cross-functional groups of scientists from several academic disciplines, in this case including the participation of experts from the natural sciences (organic chemistry, physics and chemistry of proteins, molecular and structural biology, protein engineering, systems biology, microfluid chip engineering, and nanobiotechnology), together with those in computer science (artificial intelligence, knowledge engineering) promote the innovation process in tecno-sciences by combining tacit and explicit knowledge, sharing skills, methodologies, tools, ideas, concepts, experiences, and challenges to fully explore the binomial AI–PS promising area of research (Hey et al., 2019; Mataeimoghadam et al., 2020; Senior et al., 2020; Tsuchiya and Tomii, 2020). A very recent successful case study that highlights this approach is the team of creators of system Alphafold (Senior et al., 2020; AlQuraishi, 2021), one which in the CASP (Critical Assessment of Protein Structure Prediction) competition of three-dimensional protein structure modeling were able to determine the 3D structure of a protein from its amino acid sequence. By doing so, this group of researchers solved one of natural science’s open (until now) and most challenging problems using a deep learning approach combining template-based modeling (TBM) and free modeling (FM). The key point is that the neural network prediction encompasses backbone torsion angles and pairwise distances between residues (Senior et al., 2020). At the dawn of the year 2021, this peak of the iceberg brings fresh air and a great power to the protein science field, in particular, and to the life-sciences more broadly, encouraging the new generation of scientists to work as cross-functional teams in order to tackle novel tasks toward the understanding of nature.

One challenge for the binomial AI–PS research area is to tackle the representation of tacit knowledge and include it in the ML algorithms. The relevance of tacit knowledge in the building up of protein science knowledge has come a long way since Polanyi first noted it, extending to different fields in the search for an improvement of their practical skills. In AI, the predominant way of knowledge acquisition and performance is a formal one in which the machine learns and expresses explicitly through guidelines and that works in a focalized mean; the new task alludes to a tacit dimension (Polanyi, 1962), which remains in the edge of attention and incorporates aspects that are taught and learned mostly through practice and in a comprehensive manner (it is context-specific, spreads in the laboratory environment, and comes into play in decision-making.

Some Conclusions

To sum up, the systematic review and the biochemical meta-analysis offered in this article focused on the enormous innovation that has been made in the binomial AI–PS research, both in its applications and its road maps to solve protein structures and function prediction, protein and drug design, among other tasks. The contribution of this study is 3-fold: firstly, the setup of a cross-functional group in which computer scientists, professionals in biomedicine, and a philosopher constructed a common language and together identified relevant literature in the inter-field of AI–PS and constructed a bridge between the two fields, which can serve as a framework for further research in either area.

Secondly, we stressed the importance of a finer-grain understanding of training and validation methods of ML models and their outcomes, combining databases from several areas of knowledge (life-science experiments, in silico simulations, ML, direct evolution approach, etc.) that allowed us to classify, stratify, and contribute to the evolving protein science field. Thirdly, we showed that the binomial AI–PS, a progressive research program, as Lakatos would say and has still several challenges to tackle, such as the development of a comprehensive machine learning benchmarking enterprise, the experimental confirmation of the structure of the 3D modeling in laboratories, the classification, etc., controls the vulnerability of the neural networks, the development of a tool-kit to design novel biocatalysts not found in nature using reverse engineering, human-made metabolic routes, the design of new antibody molecular factory, novel proteostasis systems, the understanding of protein folding and protein-aggregation mechanisms, etc. Finally, we suggested that there may be a paradigm shift in the AI–PS research as a result of the recent great outcome of Alphafold, encouraging its use to the new generation of scientists.

In any case, what is clear is that a cross-functional group of scientists from several knowledge domains is required to work in coordination for sharing ideas, methodologies, and challenges toward the development of road maps and computational tools, paradigms, tacit, and explicit knowledge to fully explore and close the gap of the binomial AI–PS, a promising research area.

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