RESEARCH: CANCER
FOLDING PROJECT #18724 PROFILE

This project explores how a protein called TNF-alpha works in both fighting and fueling cancer. Researchers are studying how its shape changes when it binds to another molecule, which can either help or harm cancer cells. They're using powerful computers to simulate how this protein behaves and hope to learn more about how to use it 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 involved in the body's immune system. It helps fight infections and inflammation but can also contribute to diseases like cancer and autoimmune disorders.

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Cytokine

A type of signaling molecule produced by cells.

Cytokines are small proteins that act as messengers between cells, allowing them to communicate and coordinate responses to infections, injuries, or other stimuli.

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Autoimmune diseases

Conditions where 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 and launches an attack against them. This can lead to inflammation and damage in various parts of the body.

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TNF receptor

Tumor necrosis factor receptor.

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

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Cancer

Uncontrolled growth of abnormal cells.

Cancer is a group of diseases characterized by the uncontrolled proliferation and spread of abnormal cells. These cells can invade surrounding tissues and organs, disrupting normal bodily 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 supplying oxygen and nutrients to growing tissues, but it can also play a role in tumor growth and spread.

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Inhibitor

A substance that reduces or blocks the activity of another.

Inhibitors are molecules that can bind to proteins or enzymes and interfere with their function. They are used in various applications, including drug development and research.

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Free energy landscape

A map of the potential energies of a system.

The free energy landscape represents the various possible states and their relative energies within a molecular system. It helps scientists understand how molecules move and interact over time.

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HREMD

High-resolution enhanced molecular dynamics.

HREMD is a computational technique used to simulate the movements and interactions of molecules over time with high accuracy.