VR in chemistry, a review of scientific research on advanced atomic/molecular visualization

Abstract

Atomic/molecular visualization for human sight is usually generated by a software that reproduces a 3D reality on a 2D screen. Although Virtual Reality (VR) software was originally developed for the gaming industry, now it is used in academia for chemistry teaching. This work reviews the scientific literature on 3D visualization in stereoscopic vision, the VR. VR has the capability to simulate reality since we do not observe these real particles, but it reproduces their shapes and movements digitally. The aim of this study is to present the applications of this technology and to show the function of VR in the field of chemistry and the potential for implementation of VR in research and educational settings. The review is based on 219 articles and meeting papers, between 2018 and 2020, obtained from Web of Science (WoS). A series of registers from the WoS repository was analyzed and assigned to three groups, an analysis of 2D support software, analysis of research on Virtual Reality (VR), and research on Virtual Laboratories (VL). The research on advanced atomic/molecular simulation reveals discrepancies regarding the VR effectiveness of Chemistry teaching. Novel Virtual Reality Laboratory (VRL) methodologies are emerging that have a high impact on educational and research scenarios. VL and VRL entail several advantages and drawbacks, such as the implementation of new methodologies, the increase in the students’ motivation, the growth of new spaces for collaborative online interaction, and the interaction with physical structure of any impossible, dangerous, or not feasible elements. Finally, the article compares the main features and the learning outcomes of the VRL and the traditional laboratory.

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Introduction to the molecular graphics applications

In recent years, there have emerged specific technologies for graphic digital 3D representations of atomic and/or molecular interactions that are visually viable, such as Augmented Reality (AR) and Virtual Reality (VR). AR is a mixed technology that superimposes a 3D digital image onto reality (Fombona et al., 2020b); whereas in the VR technology the user is immersed in stereoscopic vision in a fully digital environment, and it generates a highly realistic sensation as they project images or video onto the eye by detecting where the viewer directs their gaze. VR creates a simulation of reality since we do not observe these real particles, but it reproduces their shapes and movements digitally. Currently there are specific tools for each of these technologies. Nevertheless, Mixed Reality refers to an intermediate technology in the reality and virtuality continuum (Milgram et al., 1995), thus Augmented Virtuality (AV) is a subcategory that refers to the merging of real-world objects into virtual environments.

Several studies have analyzed the impact of these devices on education (Fombona et al., 2020a). However, there is ambiguous evidence of effective learning gains using Virtual Reality technology (VR). This is an exciting but under-researched area in its efficacy in educational applications (Scavarelli et al., 2021), and it appears to be in conflict within the literature as to what the best practices are for VR, specifically in certain areas such as chemistry.

A comprehensive understanding of atomic and molecular elements requires spatial and visual thinking that are sometimes lacking in traditional methodologies. Conventional teaching methodologies, with limited teaching aides, fall short in providing a detailed understanding of scientific theories and concepts related, for instance, to molecular symmetry (Achuthan et al., 2018). The correct graphical representation of the most relevant characteristics of molecular dynamics is a challenge for researchers in the industry, and especially for teachers (Torres, 2018). This situation has only recently been resolved by advances in digital management and the capacity to visualize microscopic spaces, steric effects or molecular interactions that previously only existed intangibly or in the imagination.

Molecular properties depend on the structure of the molecule i.e. arrangement of atoms, bond angles and bond lengths. The traditional simulation strategies and two-dimensional representations are being enriched with the development of entirely new predictive modeling techniques for molecular properties (Haghighatlari and Hachmann, 2019). In this sense, these resources have had to simplify intra- and intermolecular interactions to facilitate representing and understanding of this complexity (Nechypurenko et al., 2018).

Nowadays, many technologies have emerged specifically for graphic digital 3D representations of atomic and/or molecular interactions. Software such as Visual Molecular Dynamics (VMD) is usually used for modeling, visualization, and analysis of biomolecules such as nucleic acids, displaying 3D figures and built-in scripting, e.g. to simulate protein structures and their biological activity by color models and molecular trajectory animation. However, these programs seem to be most effective when combined with other applications such as Java Script for 3D visualization of biological macromolecules (Abriata, 2017), HTML on the Web with HTML5, CSS and WebGL-based tools, and in this case, with repositories and JSmol, 3dmol.js, NGL Viewer and Jolecule Protein Viewer-type Web applications. This type of online software is situated in the web server or in the “cloud”, and does not require complex computer installation; it can deliver molecular images, 3D complexes and their orbitals, enabling annotations, graphs and interactions with other webs. These technological experiments are mutually compatible, as well as with other molecular visualization tools such as PyMOL, CHIMERA and VMD (Abriata, 2017).

Virtual reality and haptic devices

New technology is affecting chemical education and industry in several ways and visual interaction can help users to acquire knowledge using a better way that is based in simulation. Now, simulation can combine the real time visualization and the haptic devices, that is, the interaction between human and external environment through seeing and touching. Virtual Reality is one of the cutting edge techniques, in which the user experiences the immersion in a complete digital environment.

The fundamental element of any VR system is a computer-generated world that perceptually surrounds the participant, and where perception is a function at least of head tracking (Slater, 2018). Immersion in a virtual system simulates the natural sensorimotor contingencies for perception, including the response to a perceptual action (O’Regan and Noë, 2001). An immersive system includes a head-mounted display with real-time motion capture head tracking, a wide field of view, high-resolution, haptic feedback, and stereo sound. The different levels of immersion correspond to different levels of illusion of being in the virtual world, and the extent to which people respond as if events in the virtual world were really happening (Slater et al., 2010). Therefore, a system that can integrate the whole body (looking around an object, bending down to look underneath something, reaching out, etc.) would be at a higher level of immersion than one that just afforded looking at a screen, for as soon as the user turns his/her head away from the screen he/she no longer perceives the virtual world (Slater, 2018).

There are several types of VR hardware available in the market e.g. (i) VR equipment, that surrounds the viewer and projects cinematographic-quality images, can be viewed on a large screen and (ii) head-mounted display (HMD) glasses such as Oculus or similar, can help the viewer to isolate themselves from external surroundings. These resources are often connected with haptic devices that enable the user to interact with digital images, through body movements and sensations. HMD glasses that have external sensors, outward-facing cameras, motion-sensing controllers, can be operated cable-free, to provide full movement tracking for both the head and the hands. These devices are connected to external display such as smartphone or computer, either by Wi-Fi or cable, or can work independently to interact with the VR images. There are haptic devices that are simple and inexpensive tools such as pencils-pointers, that can be inserted in to the smartphone and also allow a similar interaction to give 3D experience with specific VR headset.

HMD devices produce images/videos that are based on the body movements and provide a realistic immersive sensation to the viewer. Haptic devices have complementary manual controls that help the viewer to adjust the object displayed distance and it favors an interaction with the molecular models viewed by the user. Thus, the user can grasp or enlarge the molecules to measure the bond lengths and bond angles using their hands, in order to study the interactions between atoms of each molecule while user visualizing these interactions. This way, haptic devices have the ability to rotate the molecules which help to determine the stereochemistry of a structure.

It is also possible to import elements from public databases such as the Protein Data Bank, Pubchem, Drugbank, or from the user's computer. This technology shares the observer's point of view with colleagues online, and it support collaborative activities with other network users simultaneously. Thus, as a result of quantum information theory, it can extract large amounts of data from matter at the microscopic scale, and molecular representation can also encompass aspects of cooperative information networks, and this could be integrated into Big Data (Arús-Pous et al., 2019). The dataset generated, for example, in a quantum tomography sample and a wave function is too much information for the human brain to process. Hence the need to articulate procedures to manage vast quantities of data, and the synergy of computing devices can be helpful (Aspuru-Guzik et al., 2018).

Methodology

Goals and method

Technology is constantly developing, and there is little exploration in the literature on molecular advanced visualization procedures. Besides, there are other reasons that justify this research, namely the impact of these dynamic, complex technologies on Chemistry instruction and research, and they should be analyzed. Thus, the purposes of this study are:

– To provide recent scientific findings on the VR, that are currently available for viable atomic/molecular visualization.

– To give an overall view of available tools to university lecturers for the implementation in various educational environments and, more specifically, the incorporation of VR technology into chemistry studies.

– To provide some guidelines to carry out a detailed analysis in the future.

The methodological design of this study is focused on a qualitative analysis of the scientific research in this field.

Selection of the sample of documents

Web of Science (WoS) is a scientific repository belonging to Clarivate Analytics, and it contains the multidisciplinary Journal Citation Report (JCR) database, where the highest quality reviews are classified according to statistical data, and within several thematic categories.

We search for the significant registers in WoS by applying BIbExcel2016-02-.20 software to analyze to a set of reiterative keywords extracted from this database; e.g., “Virtual Reality”, “Virtuality”, “3 Dimension Visualization”, “3D”, “Stereoscopic Interface”, “Molecular Visualization Software”, “Scientific Visualization” and “Immersive Analytics”. These words were linked to “Chemistry” and the search was run to discover which of these terms extracted the registers related to “Virtual Reality, advanced atomic and molecular visualization”. The most representative keywords obtained were “Chemistry” and “Virtual Reality”, and two categorizations of registers were considered that included either of these terms in the Topic or Title of the documents analyzed; that is, those documents related to the topic were counted if these terms appeared only in the title, or if these terms appeared in the abstract, in the title or in the key words. Likewise, registers were especially analyzed if these terms were the central issue appearing in the title.

Using the WoS Database we collected information from 1900 to the present, from all over the world and information included mainly from journals, books and conference proceedings. The search descriptors, “Chemistry” and “Virtual Reality” provided 1012 documents. This relatively high amount of registers led us to reduce this size to articles and proceedings in conferences in a non-probabilistic sampling. Furthermore, we wanted to narrow down the research from specific time point become outdated.

Table 1 demonstrates manuscripts published since 2016. However, prior to 2019, most research about developments in atomic/molecular visualization was about AR. The developments of VR became more prominent after 2018 (Goddard et al., 2018). Thus, the new reference point became “registers from 1 January 2018 to 31 December 2020”, for which “Chemistry” and “Virtual Reality” appeared in 282 documents and, more specifically for this research, in 219 articles and proceedings papers as subject descriptor/topic, that is, in the keywords of the text, abstract or in the title. The definitive research sample of these 219 documents follows the algebraic expression WoS ∩ 2018 ∪ 2019 ∪ 2020 ∩ Topic ∩ “Chemistry” ∪ “Virtual Reality”, in other words, manuscripts in the WoS database, in the period of time from 2018 to 2020, containing within the topic the terms “Chemistry” and “Virtual reality”. Some of the research that supports the main ideas summarized in this article are included in the bibliographic references.

Table 1 Research papers on Web of Science

	“Chemistry” “Virtual Reality” no. documents
	… in the title, abstract or key words	… in the title
2016	28	1
2017	42	1
2018	58	3
2019	79	9
2020	60	6
2018 to 2020	282	18
Article	154(54.61%)	12(66.67%)
Proceeding	65(23.05%)	4(22.22%)
Book	2(0.71%)
Other	61(21.63%)	2(11.11%)
“All years” (1900 to 2020)	2012	35
Articles	492(48.61%)	23(65.71%)
Proceeding	300(29.64%)	6(17.14%)
Books	6(0.59%)
Other	244(24.11%)	(28.57%)

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The most of the search outcomes showed articles in scientific journals, and very small number of books, which suggest that the investigations are neither very consolidated nor published in educational texts.

Document analysis procedure

The WoS database registers were subjected to thorough content analysis in three stages, using tools such as Aquad7 which offers wide possibilities in describing the data, finding linkages, implicating and creating a data-grounded theory (Huber and Gürtler, 2013):

(1) Download registers from WoS platform then analyze the documents performing the first content analysis to determine whether they related to Virtual Reality and atomic/molecular visualization experiences. At any time, papers are downloaded from WoS website via RedIRIS (Spain) and the software of the University of Oviedo helped us to prepare each article converting text file into the format txt, constructing links, counting words, excluding and calculating frequencies.

(2) Select documents related to “Chemistry” and “Virtual Reality” that are belongs to JCR category, including only articles from this database, since JCR level groups are of advanced research. Here, it can be only documents with a high impact (measure by the number of citations per year/total citations). This procedure is widely used by academic institutions, funding agencies and researchers (Fombona et al., 2017; Quintero et al., 2019; Ferk and Mlinarec, 2021; Wu et al., 2021) to objectively quantify a scholarly influence and, consequently, how well it meets the needs of its readership.

(3) Extract outcomes of each document. The content analysis was performed by two professors who focused on reviewing the generic conclusions of each article, and each of them analyzed half of the sample. This is because they are specialists in educational documents and have several JCR publications about reviews of scientific literature. The first analysis highlighted the main outcomes of each article. Other professor is expert in chemical research and VR, thus in a similar way, he subsequently revised the significant information about chemical simulation using Virtual Reality. From these points of view, each document was analyzed a minimum of 2 times, searching information on molecular atomic visualization and extracting outcomes in educational field. All abstracts and keywords were recorded, and analyzed independently by the two researchers, the inter-rater reliability testing showed a 93.1% agreement, with a Cohen's kappa of 0.91. The main results are generally summarized in the conclusions section of the article. Outcomes and results show the most important deductions in each research. Usually, this information is related to discoveries that respond to the initial objectives of each research analyzed. Therefore, title, key words, abstract, objectives and conclusions were the target of each article. These terms were quantified and grouped.

In addition to the extraction of the related fundamental terms, this analysis includes the assessment of the importance of these keywords in each text. Thus, the measure of their relevance is objective by checking their position in the title, within the list of keywords or/and within the abstract, giving them special value when they appear simultaneously in several places.

The analyzed papers differentiated research on any aspect of chemistry, from specific reviews of scientific literature that relates chemistry, education, and atomic visualization with VR, which have particular significance. Furthermore, it was noted that the topic was developed in-depth when the descriptors appeared in the title., e.g.Sypsas and Kalles (2018).

The data were recorded in a table with a rubric quantifying the levels of positive/integration until negative/rejection. The information is grouped incorporating data on these categories:

– Academic results.

– Student motivation.

– Implementation of new methodologies (timing, collaboration, etc.).

– New tools (accessibility, hardware, etc.).

– Specific chemical practices.

Research scope limitations of the study

The research's reliability depends on reproducibility of the reported procedures and results. This is more appropriate to statistical studies than to qualitative approaches, as qualitative methods are dependent on human observation. The reliability of our research is characterized by the methodology, and how the data are analyzed and classified. Thus, we have followed several strategies (Shenton, 2004) for ensuring trustworthiness in this research:

– Examination of previous research to frame findings.

– Methodological description to allow integrity of research results to be scrutinized. Adoption of appropriate and recognized methodology: the compilations of previous scientific research. Here we followed the procedures of many prestigious investigations selected by the WoS-JCR database, with its consolidated, rigorous non-commercially biased procedures.

– Recognition of shortcomings in the study's method. Expertise, honesty and rectitude: in this sense, the authors are professors and researchers related to the subject.

– Peer scrutiny of project to reduce effect of investigator bias. Thus, the results are obtained after a triangulation analysis, since the information has been evaluated by each initial research authors, by the authors of this paper, and by the JCR reviewers. Furthermore, a separate assessor to carry out the independent assessment was also allocated. More specifically, an associate professor of Chemistry, from another university (Western New Mexico University), participated in the qualitative analysis by reviewing the information and the specific format to present data.

The validity of our analysis was checked by experts in educational field/pedagogy, experts who work in state chemical research centers, as well as experts in management of VR devices and new technologies applied to education. They verified whether the research components were suitable for achieving the goals and their compliance with scientific requirements on all levels, from correct sample choice to adequate controls at each stage. In this regard, we want to show the trustworthiness of the analysis so researchers and practitioners applying this work can understand if the research conclusions might be transferable to the educational setting (Watts and Finkenstaedt-Quinn, 2021). In terms of external validity, we must refer to the level of generalizability since it is a qualitative study (Anney, 2014), and we could indicate that its transferability comes to the high potential for extending the research ideas to other contexts, as it is an international sample, and linked to educational action transferring the results to the students. The patterns discovered can be transferred to students and to the rest of the scientific community relevant to this subject, without regard to the specific characteristics of each software.

This research aimed to present the outcomes published in the scientific literature about Virtual Reality. Thus, the results cannot be entirely representative of all the different forms of conceptualizing or experiencing this type of simulation given the variety of tools and educational scenarios available. These technological developments also constitute a highly dynamic and rapidly developing field. That said, the compilation and dissemination of the results in this study can provide a perspective of the experiments and investigations developed in Chemistry that have made the most impact, regardless of direct or indirect commercial interests, since publication of any experiment in this field can have financial and other repercussions.

The number of related investigations and reviews of scientific literature on these terms is very small, thus, this study could be an exploratory research. On the other hand, it is a multidisciplinary work that open the way for proposals with a greater range, in which the experience of the implementation of these programs by teachers and researchers could also be analyzed. Here we can highlight how this research could be interesting for different educational levels, for software developers who know of the implementation of VR in schools, for researchers who could find new guidelines, or for people who implement VR in chemistry. Another aspect is that we had to conclude the analysis in 2020 given the effects of the COVID-19 pandemic on future research output and the probable impact on the normal flow of scientific investigation.

Results

Relevance of the traditional atomic/molecular representation on 2D screens

As a result of our research work on 3D software on two-dimensional screens, we have counted about 300 programs that dedicated to develop molecular visualization on traditional 2D computer screens, most of these display systems using 3D simulations on desktop software, without a stereoscopic vision such as VR. These display appear to be still valid today, and it allows chemists to perform other functions such as Molecular Mechanical calculations, visualization of molecular orbitals and molecular surfaces, animation of normal modes of vibration and spectra, etc. Thus, the 2D technology can read Protein Data Bank PBD, Mol, XYZ, CHARMM, CIF, mmCIF files, etc.; and it can generate video files (QuicKTime, mpeg, mp4, etc.) and image in different formats (PNG, VRML-2, POVRay, BMP, pict, etc.).

Fig. 1 and 2 show examples of 2D pictures and 3D simulation on a 2D display. Some cases, for instance, visualization intramolecular motions of protein flexibility, represent animated applets where the user can modify some parts of the molecule, however this information of 3D structures is seen on 2D projections and it can prevent the disclosure of useful features (Ratamero et al., 2018).

Fig. 1 Cyclohexane Molecule. Formula: C₆H₁₂. On the left, 2D molecule drawing made by the authors. On the right, a screenshot of a PC 3D simulation made by the authors. Source: Software on line for PC (PubChem). PubChem is an open chemistry database at the National Institutes of Health (NIH).

Fig. 2 Molecule: Cyclohexane Molecule. Formula: C₆H₁₂; 3D stereoscopic and steric effect representation made by the authors with iMolview Software (iMolview© 2021 Molsoft LLC. http://www.molsoft.com) APP for smartphone, on line.

It was found that the research analyzed in this review normally used several of these traditional programs simultaneously or in a combined manner; and they emphasize the challenge of depicting molecular or atomic structures due to their complex, highly correlated and 3D structures (O’Connor et al., 2019).

Different studies showed the potential benefits of using interactive visualizations during inquiry instruction as a resource to help all students (Ryoo et al., 2018). These simulations are especially important in teaching material that involves abstract concepts that requires spatial skills such as in Organic Chemistry (Edwards et al., 2019), especially in initial learning of chemistry (Abdinejad et al., 2020). The molecular representations can show the identity of each atom, its structure, orbitals, electronic density, power, etc., visualizing the model with variations in size, distortions or rotations while using the computer keyboard, trackpad or mouse.

Currently, many of these molecular representation programs enable users to interact with the molecules, and manage different types of couplings between orbitals, bond modifications, intra and inter molecular interactions, and other relatively more complex mechanical operations.

Software such as Avogadro, Gaussian, Molden, etc. allows computational QM/MM (Quantum Mechanical/Molecular Mechanical) and DFT (Density Functional Theory) calculations, as well as the simulation of these structural features. In any case, to study a molecular system it is always necessary to prepare a data entry file, as well as the analysis of the results file. Several combinations of programs used for molecular editing and visualization, for example, PyMol with NumPy or PyLab (Romeo et al., 2020), UnityMol with Chimera (Dai et al., 2020), VMD, Rasmol, Chimera and Isolde (Ratamero et al., 2018), Molden, Avogadro, Gauss View, ChemOffice, Molekel, Chemcraft, etc.

Research papers on virtual reality representation

The analyzes of Virtual Reality (VR) describe a standard of visualization that is highly realistic in simulating the entire 3D configuration of atomic geometry, by combining software with specific hardware, Head-Mounted Display (HMD), glasses such as Oculus, Samsung Odyssey, or HTC Vive (Ratamero et al., 2018). Each VR display shows two different images simultaneous and directly onto each user's eye, achieving a stereoscopic effect. Fig. 3–5 show four examples of Virtual Reality 3D atomic/molecular software (samples taken in own test laboratory).

Fig. 3 Screenshot of a smartphone and VR software. Isomers identification activity. This software can switch to a double screen, one for each eye, for a 3D view. Source: MelChemistry software, APP for smartphone off line. Hardware: Smartphone and VR Glasses for Smartphone. Observations: the software displays images and videos, and it allows some interactions with the experiment.

Fig. 4 Source: picture from https://www.youtube.com/watch?v=oJ5tIi1JDd8 Screenshot of ARVR Molecules© Virtual Space LLC. Software APP for smartphone off line. Virtual Laboratory analyzing a Cyclohexane Molecule (C₆H₁₂). This software displays images or videos, one for the left eye, and another for the right eye, both with a slightly different point of view to represent 3D vision. It allows some interactions with the experiment. Hardware: Smartphone, and VR Glasses for Smartphone, Cardboard or similar.

Fig. 5 Shot of a 3D Virtual Reality Laboratory with two avatars (Ty and Jeremie) visualizing layers of Graphene and handling the image of the 3D molecule. Picture from Nanome Software. Nanome© 2021 Nanome Inc. This software switch to a double screen, one for each eye, this produces stereoscopic vision. Hardware: Oculus glasses.

The VR technology goes beyond the mere molecular visualization on the computer screen and become multisensory immersion (Edwards et al., 2019), especially with the combination of haptic or tactile interfaces. Some research combines 2D rendering software, such as Chimera, viewed with HMD glasses, such as HTC Vive, Oculus or Samsung, together with other software, such as AtlPDB, that enable collaborative discussions (Goddard et al., 2018).

The real chemical world has three spatial dimensions but only two in the standard modes of its capture and depiction, thus VR simulation must reproduce and adapt that complexity to the human vision and perception (Westheimer, 2011). For instance, it depicts through coordinates as latitude and longitude for representing the energy multidimensional landscape where several values of power are elevation levels (Martino et al., 2020).

Thus, the immersion in a 3D virtual world by HMD devices, allows the user to explore the analogy between the evolution of a chemical process and the associated potential energy (Martino et al., 2020). That research collect values for nuclear geometries, the Potential-Energy Surface (PES), a central experiment in many facets of chemistry such as reaction diagrams, thermodynamics, spectroscopy, and in governing the dynamics and kinetics of chemical processes.

The majority of research on practical experiences with VR relate to educational usage (Dai et al., 2020), endowing these activities with an attractive, game-like feel in recognition of gamification as a common activity among students, for example, learners enjoy the VR experience while they model basic hydrocarbon bonding molecules in Organic Chemistry (Edwards et al., 2019).

Often, the design of virtual laboratories is related to video games strategies, this could be due to the fact that many young people know VR playing video games (Pallavicini et al., 2019). Most of these developments arise from companies with an economic target, however, their projects are innovative from traditional teaching. Thus, the virtual scenarios are surrounded by a playful approach and use gamification strategies (Bibic et al., 2019), where students face challenges, missions to be carried out, and scores derived from each activity (Ratamero et al., 2018). These activities include chemical tasks with data simulation, links to extension documents, examples of the implications in real-world cases, and assessment of activities (Bibic et al., 2019). Other similar studies emphasize that this serious game-based technology improves students’ learning (Hodges et al., 2018).

The research reveals the experiences of VR software developers building new applications for devices across a range of platforms. This is the case of NARUPA (O'Connor et al., 2019), an open VR resource in Windows within Interactive Molecular Dynamics in Virtual Reality (iMD-VR) that can manipulate simulations in real time and 3D. In this case, a group of researchers share in the experiment and work together to manipulate atomically-precise molecular structures interactively, and perform common tasks such as analyzing the potential energy functions, protein–ligand binding, biomolecular conformational sampling, reaction discovery using “on-the-fly” quantum chemistry, and transport dynamics in materials. It seems that new VR software creation is a path that is being actively explored through robust testing, such as in the case of vLUME software, Visualization of the Universe in a Micro Environment, which generates large 3D single-molecule localization microscopy datasets (Spark et al., 2020), it enables segmentation and analysis of local complex geometries in 3D, that would otherwise be impossible by using regular visualization programs.

Researchers have tested these VR simulations with a range of applications, for example, in managing highly precise information in the visualization of energy functions in molecular systems, and in testing Atomic Neural Networks (ANN), generating high-quality data in the hyper-dimensional spaces of the molecule's Potential Energy Surface (PES), and making these phenomena more easily understandable (Amabilino et al., 2020). There is similar interest in the analyses of VR with database management, as in NOMAD software with HMD, HTC Vive, Samsung GearVR glasses and even the simple Google Cardboards (Garcia-Hernandez and Kranzlmuller, 2019) which have been used in the Chemistry of Materials, Theoretical Chemistry, Biochemistry and Biology, where their use is both simple and intuitive when applied to teaching and marketing.

Other VR researches with VRmol software have improved the visualization, calculation and editing of complex structures, and their intuitive perception; such experiences have also enabled interactions with data in the cloud (Xu et al., 2020), with Web resources to undertake virtual travel and exploration (Fung et al., 2019). Of particular interest are those investigations that analyze these cooperative networks, such as those based on Blockchain virtual technology and its capacity to execute computing experiments by interconnecting databases (Hanson-Heine and Ashmore, 2020).

Chemical research papers on virtual reality laboratories

Virtual Laboratories (VL) digitally recreate spaces where the student interacts with virtual tools that simulate real devices found in traditional laboratories (Fig. 4). A specific type of these labs are those that are based on Virtual Reality, in these cases, students are placed within a completely virtual setting (Firuza, 2020). There are numerous descriptions of Virtual Laboratories experiences and developments in specific software, and hardware working on digital platforms. However, there are few works that describe the Virtual Reality Laboratories (VRL) and the immersive settings with glasses, haptic connections and tactile interaction. Research has shown educational documents about HMD Oculus, and its manual control accessories (Duan et al., 2020), and other using gloves with embedded sensors, software that tracks hand and finger movements, for example, to build hydrocarbon molecules and experiment with haptic feedback. In this case, the students worked in a specific laboratory, the Virtual Reality Multisensory Classroom (VRMC), where the participants reached a high level of motivation as they felt immersed in the experiments (Edwards et al., 2019).

Some experiences are of special relevance to show experiments in immersive environments, in this sense the Interactive Molecular Dynamics in Virtual Reality (iMD-VR) allows users to interact and perform different tasks: to build protein complexes; or for instance, the interactive Claisen rearrangement of the molecular mechanics forces and the interaction in the chorismate molecules, more specifically, docking of chorismate with chorismate mutase using real-time molecular mechanics forces (Bennie et al., 2019).

Many experiences (Achuthan et al., 2018; Cataldi and Dominighini, 2018; Edwards et al., 2019; Firuza, 2020) suggest that educational activities are conditioned by the characteristics of these tools. VR technology needs to reproduce 3D scenarios with very realistic images, where the user must roam freely, and it requires high performance of computing equipment. This feature, together with the use of very specific devices, and the accelerated rate of technological change, increases the price of this technology. Besides, an extended use of VR glasses can cause visual fatigue and even nausea.

VRL communities working online

The research emphasizes increasing collaboration in scientific networks and the assimilation of alternative sources of data and virtual experiments (Davenport et al., 2018; Goddard et al., 2018; Nataro and Johnson, 2020; Winkelmann, 2020). It enriches the experience with the interaction of resources in the cloud, for example, with access to thousands of virtual molecules that boost potential and levels of flexibility by generating a new virtual space for Chemistry (Grebner et al., 2020).

Some investigations analyze online VL activities, and the students who use this collaborative technology, in a complementary way to the traditional methodology, demonstrated an increase in learning, especially working individually (Davenport et al., 2018), in this case with ChemVLab.

Home confinement during the COVID-19 pandemic forced to use virtual laboratories, and these collaborative experiences among different communities were particularly effective (Nataro and Johnson, 2020).

Moreover, online programs only work in certain circumstances, so many browsers do not support VR software, which is required to display a specific simulation (Ali and Ullah, 2020). In this sense, the Augmented Reality technology can be a cost-effective alternative to VR depictions (Schmid et al., 2020), which often need special headsets and state of the art computers, that most students do not have access to (Ferrell et al., 2019).

VRL experiences at different educational levels

Education should be thought as something that goes beyond process of teaching and learning. It involves many crucial features needed to evaluate educational performance, e.g. virtual environments play a role in relevant parameters such as learning success, factors such as motivation, self-efficacy expectations, etc. (Krug et al., 2021). Increasing positive attitudes toward science have been shown as one factor that affects academic achievement (Boda and Brown, 2020). Most of research on VR and Augmented Reality are focused on education, and therefore many registers indicate how students obtained higher academic outcomes and found these technologies very attractive especially in early instruction in Chemistry (Davenport et al., 2018; Isabwe et al., 2018; Edwards et al., 2019; Boda and Brown, 2020; Winkelmann et al., 2020); this opens up many possibilities of using the VRL for high school (Mikes and Hlavaty, 2020). But, whereas Augmented Reality is a simpler technology (Krichenbauer et al., 2018) and it seems to focus working on smartphones (Grunewald et al., 2020), VR can offer more complex experiences and it is suitable for research at the degree level or even at the industry level. In this connection, it is noted several cases for highly trained researchers who cohabit real-time simultaneous virtual sceneries to interactively visualize and manipulate the dynamics of molecular structures with atomic-level precision. For example, in this high educational level, VR allows to learn potential energy functions, biomolecular conformational sampling, protein–ligand binding, reaction discovery using “on-the-fly” quantum chemistry, etc. (O'Connor et al., 2019)

VRL and the implementation of new educational methodologies

The potential of this virtual tool seems high, and VRL can train many students at a time, training with different initial levels of access, using different learning paces, monitoring personal activities, needs and progress; creating conditions to manage to establish an itinerary or rate of customized learning for each one; and this software makes it possible to store students’ task execution data, which can be used for performance analysis and further improvement (Ali and Ullah, 2020). It favors methodological changes, and it breaks down the rigid timeframes of experiences, enabling students to repeat them and avoid any safety concerns. At the industry level, researchers can alter the duration of the practical activities, making it possible to speed up experiments to see results faster, or go back in time in case they made a mistake and want to redo an activity, also the virtual laboratory can include a digital assistant/teacher who can help permanently.

The VRL can broaden access to complex chemical experiences to users of diverse profiles, thus overriding the physical, geographical, economic constraints associated with real labs and their expensive equipment; they can now do so with a simple smartphone and the appropriate software (Bhowmick et al., 2018). However, the implementation of many VRLs has been forced by the COVID-19 pandemic, and Dunnagan and Gallardo-Williams (2020) describe the problems faced by students trying to access adequate software and hardware at home, as well as within a new format of predominantly online education. In this sense, one of the main limitations of VRL is that many of the programs contain only specific experiments where users have no control, without offering any guidance to assist students regarding the procedure; besides, some trainees cannot understand how to complete the task alone, and this happens because the software may not be adapted to different learning levels.

The students acknowledge that simulations cannot replicate the authenticity and realism associated with practical work in a real laboratory (Penn and Ramnarian, 2019), also, many tasks and instruments typical of the traditional laboratory are not reproduced in the virtual laboratory. Additionally, it is important to indicate that VR provides isolation of the user and therefore a greater concentration in each activity. However, this immersion generates mental and eye fatigue in participants after extended periods of use, usually more than 30 minutes (Ali and Ullah, 2020).

VRL and effects on academic performance

There is no consensus on the interpretation of learning outcomes with VL, and some works state that there are no significant differences between VRL and real labs (Dunnagan et al., 2019). Accordingly, even though the students taking part in the virtual experiments can complete the activity in less time, this type of process seems less useful and more difficult to implement than the real and actual physical experiment (Hensen et al., 2020), and these digital tasks reduce tactile and olfactory sensation.

Other authors (Su and Cheng, 2019; Kolil et al., 2020) indicate that the use of VRL has a significant effect on academic performance, and VR users seems to produce better analyses of the processes experienced (Astuti et al., 2020), with a sharper focus on the study of the experimental procedure rather than on the tools or equipment, as is the case in physical labs.

We can summarize the main strengths of Virtual Reality in the educational field of Chemistry:

– Security, users can perform chemical tasks without risk, alleviating anxiety caused by laboratory hazards and lack of sufficient resources (Davenport et al., 2018; Wolski and Jagodzinski, 2019; Kolil et al., 2020).

– Remote access to experiences in realistic chemistry sites such as real-world laboratories or experiments. Carrying out online learning practices opens up the possibility of Distance Education in Chemistry lab.

– Motivation in enjoyable and innovative scenarios. The user's participation is presented by an avatar, avoiding embarrassing situations, and allowing students to join group discussion and raise their hands to ask any question (Ali and Ullah, 2020).

– VL can be used to simplify complex problems, resulting in time and money savings. In this sense, it allows different modes of learning in chemistry experiments, pauses or multiple repetitions of experiences, changes and testing alternatives in experiments (Davenport et al., 2018).

The combined proposals are the most efficient, and some authors have shown that students who experience a Blended Reality Environment (BRE) gain significantly in enhanced learning and improve in the practices specified in the Next Generation Science Standards (NGSS) (Ryoo et al., 2018). Students are also able to practice scientific skills that are almost authentic within a setting that is as real as that used by scientists (Hodges et al., 2018).

Discussion

Most documents found agree on the positive attitude of users towards the VR, with students showing a high level of motivation and interest in this technology (Isabwe et al., 2018; Edwards et al., 2019; Winkelmann et al., 2020), but other points are being widely debated. The research compiled in the JCR database includes the strengths and weaknesses of Virtual Reality applied to chemistry teaching and, therefore, it seems interesting to compare in this section these results with other documents located outside the JCR level.

New software and hardware to develop VR environments

Research on VR hardware and software demonstrates how useful HMD equipment is for visualizing and sampling complex structures and dynamics with atomic-level precision. These experiments combine a range of different resources, and some illustrative cases are highlighted below, e.g., HMD VR representation by Oculus and HTC VIVE for manipulating, modeling and sampling of molecules in 3D (materials such as Methane, Helicene, Buckminsterfullerene, etc.), together with hardware like Processing Units GPU (O’Connor et al., 2018), in conjunction with Application-specific Integrated Circuits (ASIC), Cloud Computing platforms, and Distributed Computing Networks (Ibem, Google Cloud Platform, Azure, etc.). Programs such as UnityMol and ChimeraX, can be employed together, so UnityMol could be a good VR platform for teaching molecular orbitals, whereas UnityMol is interesting for fast VR sessions of data visualization (Dai et al., 2020). Additionally, there has been research on Molecular Dynamics Visualization software (MDV, PYMOLA and MinOmics), in combination with specific tools such as Hub for Immersive Visualization and eResearch, HIVE (Wiebrands et al., 2018).

On the other hand, there are few investigations on VR with wide-screen projection systems, which totally surround the viewer to enable to visualize 3D models, also with glasses and specific software. In this sense, we found some research (Müller et al., 2018; Sommer et al., 2018; Wiebrands et al., 2018) on VR Cave Automatic Virtual Environment technology (CAVE) which produces a total immersion, adjusting visualization according to the user's position and viewing direction. These experiments also analyze other VR equipment with widely used HMD devices, like Oculus (Rift, Quest), HTC Vive and Powerwalls projectors, as well as sound systems like Varjo VR-2.

Challenges with VL environments

Online work experiences and Virtual Laboratories (VL) are increasing, and consequently completely digital scenarios and environments appear. Thus, it was identified interesting data on VL trials with significant differences. VL can facilitate teacher action and improve student learning outcomes (Jiménez, 2019; Eljack et al., 2020). Nevertheless, various registers match our findings that detected no improvement in terms of academic records with VL use, or even that real lab work was better (Ratamun and Osman, 2018); e.g., there were experiences on the synthesis of inorganic compounds that indicate that VL do not improve student competence in chemical manipulation and microscopic analysis (Kurniawati et al., 2019).

Our review also found collaborative spaces in the cloud involving interaction between online computers, which are also motivational and interesting for the students but have not translated into notable improvements in academic achievement as yet. This fits with the results of practices developed in virtual worlds like Second Life which create collaborative dynamics and favorable attitudes (Winkelmann, 2020).

It is also interesting to analyze whether increased motivation improves students' academic results. There does seem to be a consensus on the use of VL prior to performing experiments in a real lab, in order to prepare and train users without space, time and cost constraints (Sypsas and Kalles, 2018; Kurniawati et al., 2019). Some articles reviewed VL APPs for use in Biology, Biotechnology and Chemistry classes, and although they reaffirm that VL must not substitute the real experience lab work, the advantages are best seen when VL is combined with traditional lab practices as they indicate good general cognitive effects in the development of skills and motivation (Cataldi and Dominighini, 2018; Sypsas and Kalles, 2018). Comparatively with the same amount of training time, there is a large increase in student achievement when the traditional methodology is combined with the virtual laboratory and tutoring led by the teacher (Agbonifo et al., 2020).

The research does not define a clear pedagogical framework, and the technological development prevents stable and lasting analyzes. A pedagogical theory goes beyond a ICT experience, it is an organized plan that defines the content to be learned in terms of clear standards of what the teacher/student should know and be able to do in a systematic way. Therefore, future research should address the effects of Virtual Reality technologies in the pedagogical framework.

Conclusion and prospects for the future research

The compilation and dissemination of the results in this study can provide a perspective of the experiments and investigations developed in Chemistry that have made the most impact, regardless of direct or indirect commercial interests, since publication of any experiment in this field can have financial and other repercussions. These results show the research on advanced atomic/molecular simulation, revealing discrepancies regarding the effectiveness of Virtual Reality (VR) applied to education. This technology generates immersion in a new digital setting, and the student can visualize certain intangible actions of molecular complexes, but VR involves complex procedures, thus it could be recommended for higher educational levels. The papers analyzed suggest that these educational activities are conditioned by the characteristics of these tools. On the one hand, this technology needs to reproduce 3D scenarios with realistic images. Here the participant can roam freely, and this requires high performance computing equipment. This feature, together with the use of very specific devices, and potential out datedness, increases the price of this technology. Besides, an extended use of VR glasses can cause visual fatigue and even nausea.

However, optimistic results are generally seen when these representations are considered in combination with different methodologies and tools, mixing traditional activities with novel lines of work (Grebner et al., 2020), such as collaborative online VR user management among a large number of researchers, ubiquitous access to compare data in the cloud, or human-machine interaction on the Internet.

Simultaneously, Virtual Laboratories (VL) are proliferating, which have several advantages and disadvantages. Recently VL and VR are united in a new technology, the Virtual Reality Laboratory (VRL). These developments imply a novelty and drive changes both in educational settings and in collaborative/industry research. In this sense, the appearance of the VRL entails the implementation of new methodologies and an increase in the levels of motivation of the students. Additionally, it constitutes a highly dynamic and rapidly developing model, consequently there is still much to explore and to learn on how to develop the full potential of this technologies in chemistry. Perhaps, this technology could be the foundation of Machine Learning where the human intervention it is controlled by machines (Haghighatlari and Hachmann, 2019; Riniker et al., 2019), although it relates to, supports, and augments traditional physics-based approaches in computational research. In agreement with other authors (Haghighatlari and Hachmann, 2019) further research into the implementation of new descriptors as well as the formulation of additional criteria will be necessary for the foreseeable future.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are thankful to the research group and the support staff, and we especially thank Professor Mr Shiva K. Kyasa, Associate Professor of Chemistry at the Western New Mexico University (Department of Natural Sciences, Silver City, EEUU).

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