RESEARCH: CANCER
FOLDING PROJECT #18721 PROFILE

The project studies tumor necrosis factor (TNF), a protein that can both help and harm cancer. Researchers want to understand how TNF works by looking at its structure and how it interacts with other molecules. They're using computer simulations to explore different shapes of TNF and see how they affect its ability to fight or promote 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 regulates inflammation and immune responses.

Tumor necrosis factor (TNF) is a protein that plays a crucial role in the body's inflammatory response. It helps fight infections and diseases but can also contribute to chronic inflammation if overproduced. TNF is involved in autoimmune disorders like arthritis and Crohn's disease, as well as certain types of cancer.

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Cytokine

A signaling molecule produced by cells of the immune system.

Cytokines are small proteins that act as messengers between cells in the immune system. They play a vital role in coordinating immune responses, such as inflammation, fighting infections, and regulating cell growth. Cytokines can be beneficial or harmful depending on their type and concentration.

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TNF receptor

Receptor for tumor necrosis factor (TNF).

The TNF receptor is a protein found on the surface of cells that binds to TNF. This binding triggers a cascade of events within the cell, ultimately influencing its behavior. There are several types of TNF receptors, each playing a specific role in immune responses.

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Autoimmune diseases

Diseases caused by the immune system attacking healthy tissues.

Autoimmune diseases occur when the body's immune system mistakenly attacks its own cells and tissues. This can lead to a wide range of symptoms depending on the affected organs. Examples include rheumatoid arthritis, lupus, and type 1 diabetes.

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Cancer

Uncontrolled growth and spread of abnormal cells.

Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. These cells can invade surrounding tissues and organs, leading to various health problems. Cancer is caused by a complex interplay of genetic and environmental factors.

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Tumor angiogenesis

The formation of new blood vessels within a tumor.

Tumor angiogenesis is the process by which tumors develop their own blood supply. New blood vessels provide nutrients and oxygen to the growing tumor, enabling its further growth and spread.

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HREMD

High-resolution Enhanced Molecular Dynamics simulations.

HREMD is a computational method used to simulate the movement and interactions of molecules in biological systems. It allows researchers to study the behavior of proteins, DNA, and other biomolecules at high resolution.