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31 August 2021 | Story Leonie Bolleurs | Photo Supplied
UFS scientists involved in revolutionary protein structure prediction
Left: Dr Ana Ebrecht, a former postdoctoral student of the UFS, was part of the team that validated the data for the Science paper. Right: Prof Dirk Opperman was involved in a revolutionary finding in biology, which predicts the structure of a protein. His work in collaboration with other scientists has been published in Science.

Prof Dirk Opperman, Associate Professor in the Department of Microbiology and Biochemistry at the University of the Free State (UFS), in collaboration with Dr Ana Ebrecht (a former postdoc in the same department) and Prof Albie van Dijk from the Department of Biochemistry at the North-West University (NWU), was part of an international collaboration of researchers who participated in solving an intricate problem in science – accurate protein structure prediction.

The team of researchers recently contributed to an influential paper describing new methods in protein structure prediction using machine learning. The paper was published in the prestigious scientific journal, Science.

“These new prediction methods can be a game changer,” believes Prof Opperman.

“As some proteins simply do not crystalise, this could be the closest we get to a three-dimensional view of the protein. Accurate enough prediction of proteins, each with its own unique three-dimensional shape, can also be used in molecular replacement (MR) instead of laborious techniques such as incorporating heavy metals into the protein structure or replacing sulphur atoms with selenium,” he says.

Having insight into the three-dimensional structure of a protein has the potential to enable more advanced drug discovery, and subsequently, managing diseases.

Exploring several avenues …

According to Prof Opperman, protein structure prediction has been available for many years in the form of traditional homological modelling; however, there was a big possibility of erroneous prediction, especially if no closely related protein structures are known.

Besides limited complementary techniques such as nuclear magnetic resonance (NMR) and electron microscopy (Cryo-EM), he explains that the only way around this is to experimentally determine the structure of the protein through crystallisation and X-ray diffraction. “But it is a quite laborious and long technique,” he says.

Prof Opperman adds that with X-ray diffraction, one also has to deal with what is known in X-ray crystallography as the ‘phase problem’ – solving the protein structure even after you have crystallised the protein and obtained good X-ray diffraction data, as some information is lost.

He states that the phase problem can be overcome if another similar-looking protein has already been determined.

This indeed proved to be a major stumbling block in the determination of bovine glycine N-acyltransferase (GLYAT), a protein crystallised in Prof Opperman’s research group by Dr Ebrecht, currently a postdoc in Prof Van Dijk’s group at the NWU, as no close structural homologous proteins were available.

“The collaboration with Prof Opperman’s research group has allowed us to continue with this research that has been on hold for almost 16 years,” says Prof Van Dijk, who believes the UFS has the resources and facilities for structural research that not many universities in Africa can account for.

The research was conducted under the Synchrotron Techniques for African Research and Technology (START) initiative, funded by the Global Challenges Research Fund (GCRF). After a year and multiple data collections at a specialised facility, Diamond Light Source (synchrotron) in the United Kingdom, the team was still unable to solve the structure.

Dr Carmien Tolmie, a colleague from the UFS Department of Microbiology and Biochemistry, also organised a Collaborative Computational Project Number 4 (CCP4) workshop, attended by several well-known experts in the field. Still, the experts who usually participate in helping students and researchers in structural biology to solve the most complex cases, were stumped by this problem.

Working with artificial intelligence

“We ultimately decided to turn to a technique called sulphur single-wavelength anomalous dispersion (S-SAD), only available at specialised beam-lines at synchrotrons, to solve the phase problem, says Prof Opperman.

Meanwhile, Prof Randy Read from the University of Cambridge, who lectured at the workshop hosted by Dr Tolmie, was aware of the difficulties in solving the GLYAT structure. He also knew of the Baker Lab at the University of Washington, which is working on a new way to predict protein structures; they developed RoseTTAaFold to predict the folding of proteins by only using the amino acid sequence as starting point.

RoseTTAaFold, inspired by AlphaFold 2, the programme of DeepMind (a company that develops general-purpose artificial intelligence (AGI) technology), uses deep learning artificial intelligence (AI) to generate the ‘most-likely’ model. “This turned out to be a win-win situation, as they could accurately enough predict the protein structure for the UFS, and the UFS in turn could validate their predictions,” explains Prof Opperman.

A few days after the predictions from the Baker Lab, the S-SAD experiments at Diamond Light Source confirmed the solution to the problem when they came up with the same answer.

Stunning results in a short time

“Although Baker’s group based their development on the DeepMind programme, the way the software works is not completely the same,” says Dr Ebrecht. “In fact, AlphaFold 2 has a slightly better prediction accuracy. Both, however, came with stunningly good results in an incredibly short time (a few minutes to a few hours),” she says.

Both codes are now freely available, which will accelerate improvements in the field even more. Any researcher can now use that code to develop new software. In addition, RoseTTAFold is offered on a platform accessible to any researcher, even if they lack knowledge in coding and AI.

News Archive

Hearing loss a silent public health crisis in South Africa
2017-03-27

Description: Hearing loss a silent public health crisis in South Africa Tags: Hearing, Deaf, World Hearing Day
Dr Magteld Smith engages on the topic of hearing loss
and how it coincides with the commemoration of
World Hearing awareness during the month of March.
Photo: Oteng Mpete 

Communication is a principal challenge for people with hearing loss. It can be difficult to negotiate everyday interactions, whether in the workplace, on the street, in classrooms, courts, during consultations with health professionals, or even when contacting the police. The World Health Organisation’s (WHO) World Hearing Day is an annual advocacy event held each year on 3 March to raise awareness and promote ear and hearing care across the world. In many countries this awareness campaign usually starts on 3 March but many continue to create awareness for the full month of March. 

Hearing loss is a global reality
According to Dr Magteld Smith, a researcher at the University of the Free State (UFS) School of Medicine’s Department of Otorhinolaryngology, unaddressed hearing loss poses a high cost for the economy globally and has a significant impact on the lives of those affected. Interventions to address hearing loss are available in South Africa but are not accessible or affordable for most citizens. This is partly because not only persons with hearing loss but also people with disabilities experience barriers in accessing services that many of us take for granted, including health, education, employment, and transport as well as information. These difficulties are exacerbated in less-advantaged communities.

“WHO estimates that there are more than 360 million persons with hearing loss globally. The statistics in South Africa are unreliable due to the different definitions used by Statistics South Africa and the absence of training of the officials who conduct and collect statistics concerning hearing loss in South Africa,” says Dr Smith. 

According to Dr Smith, analysis from retrospective studies reflects that about 17 out of 1 000 infants are born daily in South Africa with severe to profound hearing loss. However, Dr Smith states that the number could be higher because of late diagnosis, high levels of undiagnosed and untreated hearing loss. This excludes young adults, adults and the elderly as well as children with acquired (become deaf after birth) hearing loss.

Crisis that needs urgent intervention 
Dr Smith says hearing loss is an emergency which the South African government fails to prioritise. She says that research published confirms that the risk compounding the projected increase in hearing loss that comes with an ageing population. This is a looming and silent public-health crisis.
She believes that the government should take urgent action to align research-spending with the current and projected size and impact of hearing loss. It should also collaborate across related conditions, such as vision, neurodegenerative diseases and neurological conditions. Furthermore, the government needs, and is obligated, to deliver more accessible and integrated services and develop quality standards that take account of the whole pathway – linking public health, clinical and social needs.

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