RESEARCH: CANCER
FOLDING PROJECT #18712 PROFILE

This project investigates how a protein called TNF-alpha, which plays a role in both fighting and promoting cancer, changes shape when interacting with inhibitors. Researchers are using computer simulations to understand the stability of TNF-alpha and whether it can naturally adopt the inhibited form. This research could lead to new ways to target TNF-alpha for cancer treatment.

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 regulates immune responses.

Tumor necrosis factor (TNF) is a protein that plays a crucial role in the body's immune system. It helps fight infections and inflammation but can also contribute to chronic diseases like arthritis and cancer.

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Cytokine

A type of protein that signals between cells.

Cytokines are small proteins that act as messengers between cells in the immune system. They help regulate immune responses, inflammation, and cell growth.

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TNF receptor

Tumor necrosis factor receptor

The TNF receptor is a protein on the surface of cells that binds to tumor necrosis factor (TNF). This binding triggers various cellular responses, including inflammation and cell death.

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Arthritis

A condition causing inflammation of the joints.

Arthritis is a common group of disorders characterized by pain, stiffness, and inflammation in the joints. It can affect people of all ages and has various causes.

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Crohn's disease

A chronic inflammatory bowel disease.

Crohn's disease is a long-term condition that causes inflammation of the digestive tract. It can affect any part of the gut and often leads to symptoms like abdominal pain, diarrhea, and weight loss.

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Cancer

The uncontrolled growth and spread of abnormal cells.

Cancer is a group of diseases characterized by the abnormal growth and spread of cells. It can affect any part of the body and often leads to serious health problems.

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Angiogenesis

The formation of new blood vessels.

Angiogenesis is the process by which new blood vessels are formed. It's essential for normal growth and development but can also contribute to the growth of tumors.

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Metastasis

The spread of cancer cells from the primary tumor to other parts of the body.

Metastasis is when cancer cells break away from the original tumor and travel through the bloodstream or lymphatic system to other parts of the body, forming new tumors.

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HREMD

High-resolution Enhanced Molecular Dynamics

HREMD is a computational simulation technique used to study the behavior of molecules at high resolution.

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Roivant Sciences

A biopharmaceutical company.

Roivant Sciences is a pharmaceutical company focused on developing and commercializing new drugs.