RESEARCH: CANCER
FOLDING PROJECT #18716 PROFILE

This project studies how a protein called TNF-alpha works. TNF-alpha affects the immune system and can both help and hurt cancer cells. Scientists want to understand how TNF-alpha changes shape when it binds to other proteins and if these shapes affect its ability to fight or promote cancer. They're using computer simulations to figure this out.

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 inflammation.

Tumor necrosis factor (TNF) is a protein involved in the body's immune response. It plays a crucial role in fighting infections and regulating inflammation. However, too much TNF can contribute to autoimmune diseases like arthritis and Crohn's disease.

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Cytokine

A type of protein that helps regulate immune responses.

Cytokines are small proteins that act as messengers between cells in the immune system. They play a vital role in coordinating immune responses to infections, injuries, and other threats.

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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 attacks its own cells and tissues. This can lead to inflammation and damage in various organs.

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TNF receptor

A protein that binds to TNF and triggers a signaling cascade.

TNF receptors are proteins found on the surface of cells. When TNF binds to these receptors, it sets off a series of signals within the cell that can influence various cellular processes.

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Cancer

Uncontrolled growth of abnormal cells.

Cancer is a disease characterized by the uncontrolled growth and spread of abnormal cells. These cells can invade surrounding tissues and organs, disrupting normal body functions.

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Angiogenesis

The formation of new blood vessels.

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

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Apo state

The inactive or unbound form of a molecule.

Apo state refers to the inactive or unbound form of a biological molecule, such as a protein. In contrast, the active or bound form is often referred to as the holo state.

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Monomers

Individual units that make up a larger molecule.

Monomers are the individual building blocks of larger molecules, such as proteins and polymers. They can join together to form chains or complex structures.

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HREMD

High-Resolution Enhanced Molecular Dynamics.

HREMD is a computational method used to simulate the movement and interactions of molecules at a high resolution. It provides insights into protein structure and dynamics.