RESEARCH: CANCER
FOLDING PROJECT #18713 PROFILE

This project studies how a protein called TNF-alpha works in both fighting and fueling cancer. Researchers are using computer simulations to understand how TNF-alpha changes shape when it binds to other proteins, which is important for its activity. They want to know if the protein can change shapes on its own or if it needs help from other molecules. The findings could lead to new treatments for autoimmune diseases 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

A cytokine that plays a role in inflammation and immune response.

Tumor necrosis factor (TNF) is a protein that acts as a messenger between cells in the immune system. It's involved in triggering inflammation and fighting infections. However, too much TNF can contribute to chronic diseases like arthritis and Crohn's disease.

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Cytokine

A type of signaling molecule produced by cells in the immune system.

Cytokines are small proteins that act as messengers between immune cells. They help regulate the immune response by signaling inflammation, attracting immune cells to sites of infection, and coordinating the actions of different types of immune cells.

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TNF receptor

TNFR. A protein that binds to TNF.

The TNF receptor is a protein found on the surface of cells. It acts as a binding site for TNF, triggering cellular responses such as inflammation and cell death.

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Autoimmune diseases

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

Autoimmune diseases occur when the immune system mistakenly identifies the body's own cells and tissues as foreign invaders. This leads to an attack on healthy cells and tissues, causing inflammation and damage.

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Arthritis

A group of conditions that cause 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, each with its own causes and symptoms.

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Crohn's disease

A chronic inflammatory bowel disease that affects the lining of the digestive tract.

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

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Cancer

A disease characterized by uncontrolled cell growth and spread.

Cancer is a group of diseases that involve the abnormal growth and spread of cells. It can affect any part of the body and has various causes, including genetic mutations and environmental factors.

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Tumor angiogenesis

The formation of new blood vessels in a tumor.

Tumor angiogenesis is the process by which tumors grow new blood vessels to supply themselves with oxygen and nutrients. This process is essential for tumor growth and spread.

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HREMD

Homogeneous Refinement with Explicit Dynamics.

HREMD is a computational technique used to refine the structures of biomolecules (like proteins) by simulating their movement and interactions over time.