RESEARCH: CANCER
FOLDING PROJECT #18711 PROFILE

This project studies tumor necrosis factor (TNF), a protein that can both help and hurt cancer cells. Scientists are using computer simulations to understand how TNF works and how it interacts with its target. They want to figure out if blocking TNF's activity could be a new way to treat cancer.

Note: This TLDR is a simplication and may not be 100% accurate.

Tumor necrosis factor α (TNFα) is a cytokine that belongs to a superfamily of trimeric proteins.

This protein has been shown to be important in regulating autoimmune diseases such as arthritis and Crohn’s disease through interactions with the TNF receptor.

In regard to cancer, TNF is a double-dealer.

On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates cancer cells’ growth, proliferation, invasion and metastasis, and tumor angiogenesis.

On the other hand, TNF could be a cancer killer.

In it’s apo state TNFα has shown to be symmetrical, but small ligand inhibitors bind the TNFα disrupt this symmetry by forcing one of the monomers to be below the other two, which disrupts the binding interface to form the TNFα-receptor complex.

In this project, we want to determine the stability of the trimer and get a sense of the free energy landscape.

We also want to determine if the asymmetry found in the inhibited conformation requires the presence of an inhibitor or if the apo trimer can visit inhibited states in the absence of the ligand.

In particular we are interested in learning about the effect the volume of the binding pocket has on forming the asymmetrical TNFα complex.

The initial starting structures are 50 diverse seeds from HREMD simulations started from a crystal structure.

This is a project run by Roivant Sciences (formerly Silicon Therapeutics) as was officially announced in this press release: https://foldingathome.org/2021/04/20/maximizing-the-impact-of-foldinghome-by-engaging-industry-collaborators/ All data is being made publicly available as soon as it is received at https://console.cloud.google.com/storage/browser/stxfah-bucket.

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Tumor necrosis factor

A cytokine that plays a role in inflammation and immunity.

Tumor necrosis factor (TNF) is a protein involved in the body's immune response. It can trigger inflammation and help fight infections. However, it can also contribute to chronic diseases like arthritis and cancer.

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Cytokine

A type of signaling molecule produced by cells.

Cytokines are small proteins that act as messengers between cells. They play a crucial role in the immune system, helping to coordinate the body's response to infections and injuries.

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Arthritis

A group of disorders causing inflammation and pain in the joints.

Arthritis is a common condition that affects the joints, causing pain, stiffness, and swelling. There are many types of arthritis, each with different causes and symptoms.

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Crohn’s disease

A chronic inflammatory bowel disease.

Crohn's disease is a long-term condition that causes inflammation in the digestive tract. It can affect any part of the digestive system, from the mouth to the anus.

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Cancer

A group of diseases involving abnormal cell growth.

Cancer is a disease where cells grow uncontrollably and spread to other parts of the body. It can affect any organ or tissue.

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Tumor angiogenesis

The formation of new blood vessels within a tumor.

Tumor angiogenesis is the process by which tumors grow new blood vessels to supply themselves with nutrients and oxygen. This process is essential for tumor growth and spread.

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TNF receptor

A protein that binds to tumor necrosis factor.

The TNF receptor is a protein on the surface of cells that binds to tumor necrosis factor (TNF). This binding triggers a cascade of events that can lead to inflammation and cell death.