RESEARCH: CANCER
FOLDING PROJECT #18715 PROFILE

This project explores how a protein called TNF-alpha works in both fighting and promoting cancer. Scientists are using computer simulations to study how TNF-alpha changes shape when it binds to other proteins, and how this affects its ability to stimulate or inhibit tumor growth. This research could lead to new treatments for 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 immune responses.

Tumor necrosis factor (TNF) is a protein involved in regulating the body's immune system. It can trigger inflammation and help fight infections but also contribute to autoimmune diseases like arthritis.

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Cytokine

A type of signaling molecule produced by cells of the immune system.

Cytokines are small proteins that act as messengers between cells of the immune system. They help coordinate the body's response to infections and other threats.

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Autoimmune diseases

Conditions in which the immune system attacks healthy tissues.

Autoimmune diseases occur when the body's immune system mistakenly identifies its own cells and tissues as foreign invaders. This leads to an attack on healthy cells and organs.

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Arthritis

A group of conditions 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

An inflammatory bowel disease that affects the digestive tract.

Crohn's disease is a chronic condition that causes inflammation of the digestive tract. It can affect any part of the gut, from the mouth to the anus.

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Cancer

A group of diseases characterized by uncontrolled cell growth.

Cancer is a group of diseases where abnormal cells grow and divide uncontrollably. This can lead to the formation of tumors and the spread of cancer to other parts of the body.

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Tumor angiogenesis

The formation of new blood vessels that supply a tumor.

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

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TNF receptor

A protein that binds to TNF and mediates its effects.

TNF receptors are proteins on the surface of cells that bind to TNF. This binding triggers a variety of cellular responses.

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HREMD

High-resolution Enhanced Molecular Dynamics simulations

HREMD is a type of computer simulation used to study the movement and interactions of molecules. It provides detailed information about the structure and dynamics of biomolecules.