RESEARCH: CANCER
FOLDING PROJECT #18719 PROFILE

This project investigates how the protein TNF-alpha interacts with its receptor, which is important for regulating autoimmune diseases and fighting cancer. Scientists are using computer simulations to understand how the shape of TNF-alpha changes when it binds to a receptor, and how this binding affects tumor growth. The goal is to learn more about how TNF-alpha works and potentially develop new drugs based on these findings.

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 immune responses.

Tumor necrosis factor (TNF) is a protein involved in the body's immune system. It helps fight infections but can also cause inflammation. This can be helpful when fighting off diseases but harmful in conditions like arthritis.

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Cytokine

A small protein that is secreted by cells and acts as a signaling molecule.

Cytokines are like messengers in the body's immune system. They help cells communicate with each other to fight off infections and heal wounds.

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Autoimmune diseases

Conditions in which the immune system attacks the body's own tissues.

Autoimmune diseases occur when the body's immune system mistakes healthy cells for invaders and attacks them. This can cause inflammation and damage to various organs.

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Arthritis

A group of conditions that cause inflammation and pain in the joints.

Arthritis is a common condition that causes pain, stiffness, and swelling in the joints. It can affect people of all ages.

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Crohn’s disease

A chronic inflammatory bowel disease that affects the digestive tract.

Crohn's disease is a serious condition that causes inflammation in the digestive tract. This can lead to symptoms such as abdominal pain, diarrhea, and weight loss.

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Cancer

A group of diseases characterized by the uncontrolled growth and spread of abnormal cells.

Cancer is a disease that occurs when cells in the body grow uncontrollably. This can lead to tumors forming and spreading to other parts of the body.

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Tumor angiogenesis

The formation of new blood vessels that supply tumors.

Tumor angiogenesis is the process by which tumors develop their own blood supply. This allows them to grow and spread.

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TNF receptor

A protein that binds to TNF and mediates its effects.

The TNF receptor is a protein on the surface of cells that receives signals from TNF. This can trigger various responses, including inflammation.