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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

UFS hosts consortium to discuss broadening subcontinent’s food base
2017-03-14

Description: Cactus Tags: Cactus

The Steering Committee of the Collaborative
Consortium for Broadening the Food Base comprises,
from the left: Prof Wijnand Swart (UFS),
Dr Sonja Venter (ARC) and Dr Eric Amonsou (DUT).
Photo: Andrè Grobler

There is huge pressure on the agricultural industry in southern Africa to avert growing food insecurity. One of the ways to address this is to broaden the food base on the subcontinent via crop production. Climate change, urbanisation, population growth, pests and diseases continually hamper efforts to alleviate food insecurity. Furthermore, our dependence on a few staple crops such as maize, wheat, potatoes, and sunflower, serve to exacerbate food insecurity.  

Broadening the food base  
To address broadening the food base in southern Africa, scientists from the University of the Free State (UFS), the Durban University of Technology (DUT) and the Agricultural Research Council (ARC) have formed a Collaborative Consortium for the development of underutilised crops by focusing on certain indigenous and exotic crops. The Consortium met at the UFS this week for two days (6, 7 March 2017) to present and discuss their research results. The Principal Investigator of the Consortium, Prof Wijnand Swart of the Department of Plant Sciences in the Faculty of Natural and Agricultural Sciences, said awareness had risen for the need to rescue and improve the use of orphan crops that were up to now, for the most part, left aside by research, technological development, and marketing systems.  

"Many indigenous southern African
plant grains, vegetables and tubers
have the potential to provide a variety
of diets and broaden the household
food base.”

Traditional crops Generally referred to as alternative, traditional or niche crops, five crops are being targeted by the Consortium, namely, two grain legumes, (Bambara groundnut and cowpea), amaranthus (leaf vegetable), cactus pear or prickly pear and amadumbe (a potato-like tuber). Swart said these five crops would play an important role in addressing the food and agricultural challenges of the future. “Many indigenous southern African plant grains, vegetables and tubers have the potential to provide a variety of diets and broaden the household food base.” The potential of the many so-called underutilised crops lies not only in their hardiness and nutritional value but in their versatility of utilisation. "It may be that they contain nutrients that can be explored to meet the demand for functional foods," said Swart.

Scientific institutions working together
The Collaborative Consortium between the three scientific institutions is conducting multi-disciplinary research to develop crop value chains for the five underutilised crops mentioned above. The UFS and ARC are mainly involved in looking at production technologies for managing crop environments and genetic technologies for crop improvement. The DUT is focusing on innovative products development and market development.  

 

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