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UFS scientists involved in revolutionary protein structure prediction

31 August 2021 | Story Leonie Bolleurs | Photo Supplied

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

In January 1, 2003, the Qwa-Qwa campus of the University of the North (Unin) was incorporated into the University of the Free State (UFS).

2003-02-07

FREDERICK FOURIE

IN January 1, 2003, the Qwa-Qwa campus of the University of the North (Unin) was incorporated into the University of the Free State (UFS).

While this is merely the beginning of a long and complex process, it does represent a major milestone in overcoming the apartheid legacy in education, realising the anti-apartheid goal of a single non-racial university serving the Free State.

The incorporation is also part of the minister's broader restructuring of the higher education landscape in South Africa - a process which aims to reshape the ideologically driven legacy of the past.

In contrast to the past educational and social engineering that took place, the current process of incorporating the Qwa-Qwa campus of Unin into the UFS is informed by three fundamentally progressive policy objectives, clearly outlined in the education white paper 3: (A framework for the transformation of higher education):

To meet the demands of social justice to address the social and structural inequalities that characterise higher education.

To address the challenges of globalisation, in particular the role of knowledge and information processing in driving social and economic development.

To ensure that limited resources are effectively and efficiently utilised, given the competing and equally pressing priorities in other social sectors.

Besides informing the way the UFS is managing the current incorporation, these policy objectives have also informed the transformation of the UFS as an institution over the past five years.

In 2001, former president Nelson Mandela lauded the success of the UFS in managing this transformation, by describing the campus as a model of multiculturalism and multilingualism. This was at his acceptance of an honorary doctorate from the UFS.

Indeed our vision for the Qwa-Qwa campus as a branch of the UFS is exactly the same as it is for the main UFS campus - a model of transformation, academic excellence, community engagement and financial sustainability, building on the histories and strengths of both the Qwa-Qwa campus and the UFS (Bloemfontein campus).

Realising this vision will be a giant leap forward in establishing a unified higher education landscape in the Free State.

In more concrete terms, the UFS is working towards this vision by focusing on the following areas of intervention: access and equity; academic renewal; investment in facilities; and sound financial management.

These interventions are being made not to preserve any vestiges of privilege or superiority, but precisely to increase access for students from poor backgrounds and to promote equity and representivity among all staff.

The current growth phase of the UFS has seen student enrolment almost double over the past five years, in particular black students, who now constitute approximately 55 percent of the student population of nearly 18 000 (including off-campus and online students).

But it has not just been a numbers game. Our approach has been to ensure access with success.

Our admissions policy, coupled with the academic support and "career preparation" programmes we offer, have resulted in significant successes for students who otherwise would not have been allowed to study at a university.

This will be continued at Qwa-Qwa as well.

Our academic offerings too have undergone dramatic change. We have become the first university in the country to offer a degree programme based on the recognition of prior learning (RPL).

This is not just a matter of academic renewal but of access as well, especially for working adults in our country who were previously denied a university education.

As for the sound financial management of the UFS (including the Qwa-Qwa campus), this is being done not for the sake of saving a few rands and cents, but for the greater value to our society that comes from having sustainable institutions.

It is sustainable universities that can make long-term investments to fund employment equity, provide information technology for students, upgrade laboratories, construct new buildings, develop research capacity, and provide a safe environment for students and staff, as is happening now at the UFS.

As a result of such management, a practical benefit for prospective students at the Qwa-Qwa campus of the UFS will be lower academic fees in some cases compared with the Unin fees.

As is the case with all these processes, there are concerns from staff and students at Qwa-Qwa and the broader community of the region that the Qwa-Qwa campus serves.

To get the campus viable and to ensure its continuation in the short term, tough choices had to be made by the minister of education regarding which programmes to offer and fund.

But we have been encouraged by the community's understanding that these concerns can be addresed over time as the campus becomes financially viable.

Meetings between the top mangement of the UFS and community representatives, staff and students at Qwa-Qwa have laid the basis for building a climate of trust in such a complex process.

We should not be captives of the past divisions but build this new unified higher education landscape that can meet our country's developmental needs.

It should be a higher education landscape that is based on broadening access, promoting equity and social justice, developing academic excellence, and the effective and efficient management of scarce resources. This should be our common common objective.

Professor Frederick Fourie the rector and vice-chancellor of the University of the Free State (UFS)

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