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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

University community join hands in the walk for peace and justice
2016-03-02

Description: Prayer walk Callie Human Centre Tags: Prayer walk

The Campus Ministries Forum and South African Council of Churches (Free State) have organised a walk for peace and justice from the Main Building to the Callie Human Centre on the Bloemfontein Campus of the University of the Free State (UFS) on Tuesday 1 March 2016. This walk was followed by a prayer meeting at the Callie Human Centre.

Pastors from the Campus Ministries Forum of the South African Council of Churches (Free State) led a group of more than 350 students and staff in praise and worship, followed by prayers in English, Afrikaans, and Sesotho.

A significant gesture at the event was the church leader’s plea for peace and solutions for the conflict at the UFS.

Bishop Monty Mabale, Chairperson of the South African Council of Churches, read an extract from the declaration compiled by the pastors ministering to staff and students at the UFS.

“We are saddened by the violence and vandalism that took place on and off campus.  We understand that there are many reasons for frustration and anger, which lead to tensions at the end of last year and again now. We also understand that there are different perspectives on these developments and the complexities underlying to this. However, we cannot agree with the hate speech, the continuous blaming of others, the instigation of violence, and the damage being caused to this precious institution and its commitment to the ideal and practices of reconciliation and a proper education for every student.

“Because we believe in the justice and mercy of God in Christ, let us seek His justice in a compassionate way. Let us resolve to glorify his name in the way we enter into dignified discussions when addressing those matters we perceive to be injustices, and seek for solutions. Let us be critical of our own biased perceptions, opening ourselves to the practice of listening to the viewpoints of others and learning from each other, while discerning the will of God in our society together,” Bishop Mabale said.

The forum and council also wrote a special prayer for UFS students, staff, parents, and management:

Our Father in Heaven
•    You have created us all as unique, special people, each with a great destiny.
•    You have an awesome plan for our University, and value every person working and studying here.
•    We have not respected Your heart and opinion of everyone on campus, and so we have sinned against You.
•    Forgive us where we did not follow Your example of reconciliation, restoration, and forgiveness through the blood of Christ, Your Son, on the cross. We need You to show us what You expect of us: grace, mercy, respect, and tolerance for one another from a place of gratefulness and humility.
•    We are grateful for the opportunity and honour You have given us to be involved in this institution.
•    We repent and accept afresh Your commandment to love You and to love our neighbour as we love ourselves.
•    You are saying to us: “For I know the plans I have for you," declares the LORD, "plans to prosper you and not to harm you, plans to give you hope and a future.” We, as an institution, believe and receive this promise You gave to us.

In Jesus Name we pray,
Amen.

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