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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

Researcher at Qwaqwa Campus, Dr Aliza le Roux, selected as SAYAS member
2014-09-12

 

Dr Aliza le Roux

Dr Aliza le Roux, senior lecturer in the Department of Zoology and Entomology on the Qwaqwa Campus of the University of the Free State (UFS), was selected as a member of the 2014 South African Young Academy of Science (SAYAS). Dr Le Roux, a member of the Vice-Chancellor's Prestige Scholars Programme at the UFS, is also a South African National Research Foundation-rated (NRF) scientist (Y2) and the winner of the UFS Vice-Chancellor’s Excellence in Teaching Award in 2013.

She sees her selection to SAYAS as a unique opportunity to help change the face of science in South Africa. Dr Le Roux hopes to use her skills as project leader in social media, as well as her own learning experiences on a rural campus, to inspire especially ecological research in a country so rich in its own natural heritage.

The SAYAS selection committee was impressed by the high level of academic merit and depth of the nominations they received. “Your membership is critical in contributing to many of the vital activities and functioning of SAYAS, and we look forward to your active contributions to the further development and growth of the Young Academy,” said Prof Aldo Stroebel, Chair: SAYAS Selection Committee.

Prof Corli Witthuhn, Vice-Rector: Research at the UFS, said, “Aliza le Roux is an outstanding young scientist on our Qwaqwa Campus. She is not only an outstanding researcher but has also received prizes during the past year for her dedication to teaching. I am very excited about the young researchers on our Qwaqwa Campus with Aliza as one of the leaders, and I am looking forward to what else they can achieve in the next five years.”

In the past decade, Dr Le Roux focused her research on the cognitive and communicative skills of wild mammals in South Africa and Ethiopia. She spent four years as a postdoctoral research fellow at the University of Michigan, leading to ground-breaking research on the cognitive and communicative underpinnings of gelada monkey behaviour. Her current work encompasses an NRF-funded project on paternal care in bat-eared foxes, and experimental research on spatial cognition in wild samango monkeys. She is also involved in discussions with the Endangered Wildlife Trust to research the mitigation of road-kill incidents in South Africa.

Dr Le Roux hopes to combine cognitive ecology with more applied conservation questions in order to raise the profile of behavioural ecology as a discipline. She believes strongly in involving the public with scientific research, and has blogged for Nature Magazine on her adventures as field biologist. Her work has since found its way into numerous websites, magazine and newspaper articles and she has been interviewed on radio and BBC World.

Dr Le Roux will be inaugurated as SAYAS member on 14 October 2014.

Dr Marieka Gryzenhout from the Department of Plant Sciences is also a member of SAYAS.


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