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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

Childhood passion becomes a successful career
2016-12-19

Description: Dr Thapelo Makae Tags: Dr Thapelo Makae 

Dr Makae took up his studies at the South Campus
of the UFS, and now serves as a community vet in Tshwane.
Photo: Anja Aucamp


Dr Thapelo Makae’s youthful passion has been a driving force in his chosen career. He says: “Like any veterinarian, my love for animals started from childhood. Growing up, I always asked myself why animals didn’t have doctors like we kids did, when our pets fell ill or died.” While veterinary services were unknown where he was raised in the Phelindaba location in Mangaung, Bloemfontein, Dr Makae started doing his own research as early as Standard 1 (Grade 3). He affirms, “I’ve always wanted to help these creatures that, it seemed, no one could help.”

Having started his academic journey on the South Campus in the CPP (as the University Preparation Programme was then known), Dr Makae obtained an undergraduate degree in Agriculture, later completing an honours degree in Agriculture. “It was at this stage,” he says, “that I was recruited by Prof Johan Greyling and the late Dr Luis Schwalbach. With their support, I completed my MSc Agric, besides having the opportunity to be a junior lecturer in Animal Physiology. Dr Schwalbach was my supervisor, my mentor, and a veterinarian himself, and I worked very closely with him. He encouraged me to pursue my passion and the dream to go ahead and study Veterinary Medicine.”

Realising that dream, Dr Makae is now employed at the Gauteng Department of Agriculture and Rural Development as a community veterinarian. Among his many responsibilities, he is charged with serving the communities of the Tshwane Metro, where he visits farmers, assisting them with health and vaccination plans, and providing advice to help them develop their skills.

Dr Makae also seeks opportunities to pass on his dream. “What I am most passionate about is going to schools and giving talks to schoolchildren, especially those from previously disadvantaged communities, who might not know much about Veterinary Medicine,” he says.

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