RESEARCH: CANCER
FOLDING PROJECT #18717 PROFILE

This project studies TNF-alpha, a protein involved in both fighting and fueling cancer. Researchers are using computer simulations to understand how TNF-alpha changes shape when it binds to other proteins, and how this affects its ability to promote or stop tumor growth. The goal is to find new ways to use TNF-alpha to treat cancer more effectively.

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 involved in inflammation and immune responses.

Tumor necrosis factor (TNF) is a protein that plays a crucial role in the body's immune system. It helps to fight infections and control inflammation. However, when TNF is overproduced, it can contribute to diseases like arthritis and Crohn's disease.

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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 vital role in regulating the immune system, inflammation, and cell growth.

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Autoimmune diseases

Diseases where the immune system attacks the body's own tissues.

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

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Arthritis

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

Arthritis is a common condition that affects the joints, causing pain, stiffness, and swelling. There are many different types of arthritis, including osteoarthritis and rheumatoid arthritis.

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Crohn's disease

A chronic inflammatory bowel disease.

Crohn's disease is a serious condition that causes inflammation in the digestive tract. Symptoms can include abdominal pain, diarrhea, and weight loss.

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Cancer

A disease characterized by uncontrolled cell growth.

Cancer is a group of diseases that involve abnormal cell growth and spread. It can affect any part of the body.

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TNF receptor

Tumor necrosis factor receptor

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

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HREMD

High-resolution explicit molecular dynamics simulations

HREMD is a computational method used to simulate the movement of atoms and molecules in biological systems at high resolution.

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Roivant Sciences

A biopharmaceutical company developing new therapies for various diseases.

Roivant Sciences is a publicly traded company that focuses on developing and commercializing new drugs. They have multiple subsidiaries working in different therapeutic areas.