Pawsey Supercomputing Centre, University of Western Australia and an Indian team of researchers collaborated to model how black tea may reduce harmful effects of epigenetic modulations from inorganic arsenic, one of the world’s most common and deadly groundwater contaminants.
Inorganic arsenic is a pollutant in the groundwater of many countries, including China, the United States, India and countries in South America. Over 140 million people in 50 countries drink water laden with inorganic arsenic higher than the World Health Organisation’s recommended limit.
Inorganic arsenic damages DNA by creating reactive oxidative species in the cell. Furthermore, inorganic arsenic may induce harmful epigenetic modulations in cells, resulting in progression of cancer. Epigenetic modulations are triggered by environmental agents like inorganic arsenic, and disturb the normal functioning of cells through overexpression of harmful genes and underexpression of beneficial genes.
Professor Amitava Datta is a researcher at University of Western Australia’s Department of Computer Science and Software Engineering. He worked with a team of researchers from Chittaranjan National Cancer Institute and Calcutta University, India, to study how black tea extract could reduce the harmful epigenetic effects inorganic arsenic has on living cells.
“Arsenic contamination is a problem in many parts of the developing world, particularly in the subcontinent and in India. One of the cancers that occurs due to arsenic exposure is a kind of skin cancer called squamous cell carcinoma.”
Studies based on mouse model showed that mice administered arsenic and black tea extract had reduced instances of cancer than a control group only given arsenic. This was partly thought to be due to chemicals in the black tea extract interfering with proteins involved in harmful epigenetic modulations due to inorganic arsenic. In particular, a protein called JARID1B is known to be an epigenetic modulator that reduces the expression of beneficial genes in tumor tissues, called tumor suppressor genes. Overexpression of JARID1B has been implicated in several cancers including melanoma, and is a potential target for developing drugs for chemotherapy in cancer treatment. Black tea seems to have no effect on the expression levels of JARID1B, yet the mice group that was administered both arsenic and black tea did not develop squamous cell carcinoma. Hence the team made a hypothesis that compunds present in black tea may be inhibiting JARID1B from its cancer causing epigenetic effects.
Despite evidence that black tea extract could reduce the risk of cancer, there is limited research into exactly how it reacts with proteins in living cells to accomplish this. In particular, this is the first study on the epigenetic modulations caused by inorganic arsenic.
It was known that chemicals in black tea extract called theaflavin compounds are transported into the nucleus where they interfere with several proteins involved in epigenetic modulations. The crystal structure of the JARID1B protein showed theaflavin compounds could “dock” into the protein’s active site responsible for epigenetic modulation, stopping the protein from acting and reducing the onset of cancer in mice given black tea extract.
“We hypothesized that black tea extract was inhibiting JARID1B. To test this, we had to look at every [black tea] molecule’s three-dimensional structure. Then we studied the three-dimensional structure of JARID1B to see which molecules could successfully dock”
While this was promising, Amitava’s group took the research a step further, to model how theaflavin compounds bind to the protein inside the body, where proteins and molecules are constantly vibrating and altering their forms.
“To determine the stability of the docking, we have to look at a similar environment to the body. There are fluctuations in a normal body temperature, molecules are vibrating and polar bonds are stretching and breaking. The only way of showing stability is to do molecular dynamical simulations. These simulations are extremely expensive computationally.”
To make the modelling possible, Amitava worked with Pawsey’s Magnus supercomputer. Running the supercomputer for 24 hours, he was able to simulate how the theaflavin molecules might interact with the JARID1B protein in the constantly changing conditions of the human body.
“First, I prepared some basic conditions on my laptop, to do a simulation of theaflavin compounds (ligand) docked at the active site of JARID1B (protein) for about five picoseconds. To accomplish this, I had to run the program on my laptop for about half an hour. For the research community to accept that the docking has stability over time, you need to show stability over at least tens-of-nanoseconds. By running Magnus for 24 hours, I could simulate 45 nanoseconds of the protein-ligand docking system.”
Amitava’s model showed that theaflavin compounds were able to dock with a high degree of stability at the active site of the JARID1B protein while conditions are similar to a living cell. This evidence reinforces existing knowledge of how inorganic arsenic contributes to cancer through the JARID1B protein in human cells. It also helps to show how black tea extract might successfully block the JARID1B protein and reduce the risk of cancer.
This research demonstrates that black tea extract may mitigate some of the adverse health risks associated with inorganic arsenic. It opens the door for new medical discoveries to combat cancers, including squamous cell carcinoma and melanoma.
The molecular dynamical simulations Amitava utilised need tremendous amounts of computational power to yield results the scientific community accepts. His findings were made possible through access to Pawsey Supercomputing Center.
Read the research paper here: https://doi.org/10.1016/j.heliyon.2022.e10341
See an animation of theaflavin docked with JARID1B between 30-32 nano seconds of docking here: https://www.youtube.com/shorts/PoOwL66wPqA
See an animation of theaflavin-3,3′-digallate with JARID1B between 30-32 nano seconds of docking here: https://www.youtube.com/shorts/aS6aD4BEtGg