RESEARCH: CANCER
FOLDING PROJECT #18714 PROFILE

This project explores how tumor necrosis factor alpha (TNFα), a protein involved in both fighting and fueling cancer, changes shape when it binds to its target. Researchers are using computer simulations to understand how TNFα's structure affects its ability to interact with cells and potentially treat diseases like arthritis and 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 α

TNFα

Tumor Necrosis Factor alpha (TNFα) is a protein that plays a key role in the body's immune response. It can trigger inflammation and help fight infections, but it can also contribute to autoimmune diseases.

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Cytokine

Signaling molecule produced by cells of the immune system

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

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Autoimmune disease

A condition where the immune system attacks the body's own tissues

Autoimmune diseases occur when the body's immune system mistakenly identifies healthy cells and tissues as foreign invaders, leading to an attack on these tissues. Examples include rheumatoid arthritis, lupus, and type 1 diabetes.

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Arthritis

Joint inflammation and pain

Arthritis is a general term for conditions that cause inflammation in the joints, leading to pain, stiffness, swelling, and reduced mobility. There are various types of arthritis, such as osteoarthritis and rheumatoid arthritis.

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Crohn’s disease

Chronic inflammatory bowel disease

Crohn's disease is a chronic inflammatory bowel disease that can affect any part of the digestive tract, from the mouth to the anus. It causes inflammation, pain, diarrhea, and other symptoms.

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Cancer

Uncontrolled cell growth and spread

Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. It can affect various organs and tissues in 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 new blood vessels to provide themselves with oxygen and nutrients for growth. This process is essential for tumor development and spread.

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Inhibitor

A molecule that binds to and reduces the activity of a target protein

Inhibitors are molecules that can block or reduce the activity of specific proteins. They are widely used in drug development to target disease-causing proteins.

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Apo trimer

The TNFα molecule without a bound ligand

An apo trimer refers to the natural, unbound form of the TNFα protein. It exists as a three-unit structure (trimer) and is capable of interacting with its receptor when a ligand binds.