Researcher develops method for protein-protein structure prediction

A Nigerian researcher, Muinat Zubair, has developed a method for predicting protein structure and protein-protein interactions using a combination of experimental and computational approaches.

Zubair made this discovery during her time as a graduate teaching and research assistant at Tennessee Technological University, USA, where she got her MSc in chemistry.

Speaking about her work, she said her research is part of the efforts to solve the protein folding problem that has plagued scientists for over 50 years.

Zubair said: “I used artificial intelligence software to predict the full-length structures and interaction between two mammalian enzymes.”

“These proteins are part of the larger mitogen-activated protein kinase (MAPK) pathway that is activated in response to cellular stress. Their malfunction aggravates the symptoms of several neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, to mention a few,” she explained.

“Understanding the structures of these proteins and how they bind and activate each other will help us develop therapeutic targets to manage these diseases and improve the outcomes for patients and their families,” she added.

According to her, neurodegenerative diseases are fast becoming a global pandemic affecting millions of people globally.

“The number is only going to increase as the population of older adults increases worldwide.

“The steady-state kinetics of these proteins have never been studied. Supervised by Dr Xuanzhi Zhan, I determined their apparent Michaelis-Menten parameters through kinase assays and Western blot quantification,” she explained.

“I also predicted their full-length structure and protein-protein interaction using AlphaFold2 and AlphaFold-Multimer, two emerging software for elucidating the structure and behaviour of proteins and other macromolecules.

“Prior to this, X-ray diffraction studies have been used to solve only the structure of the kinase domains of these proteins. We also know from previous research data that other parts of the enzymes contribute to binding and activation of the protein, hence the need to predict the entire structure,” Zubair added.

She said the results of this experiment were validated using other computational software.

Explaining the process, she said, “I used molecular dynamics to test and validate the stability of the proteins and also performed protein frustratometer analysis, contact mapping, and other assessments on the interface between the docked proteins. The protein structures remained stable under simulated physiological conditions.

“Besides pioneering kinetic data on the MAPK, the computational methods I used can be applied to the study of other proteins. However, most computational work needs to be validated by wet laboratory experiments. That is the next stage of the project: site-directed mutagenesis and studying the other two isoforms of the enzyme to validate our results further.”

Zubair, who is from Iganna in Oyo State, Nigeria, grew up in Ibadan. She got her first degree in biochemistry from the Ladoke Akintola University of Technology (LAUTECH), Nigeria.

She is currently a doctoral student in the highly selective Purdue University Interdisciplinary Life Science program (PULSe), and was awarded the highly competitive and prestigious Lynn Fellowship towards her PhD.

“I hope to keep working in human health, particularly in neurodegenerative diseases. I find so much fulfilment knowing that I could potentially discover a druggable target or help understand a disease better,” Zubair added.

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