RESEARCH: INFLUENZA
FOLDING PROJECT #12429 PROFILE

Miniprotein drugs are being designed to fight flu by blocking the hemagglutinin protein on the virus. Scientists want to use computer simulations to understand how these miniproteins bind to hemagglutinin and how changes in their structure affect their binding strength. This will help them design even better miniproteins to treat influenza.

Note: This TLDR is a simplication and may not be 100% accurate.

Designed miniprotein therapeutics occupy the middle ground between small molecule drugs and monoclonal antibody treatments for infectious disease.

Hemagglutinin is a viral fusion protein that allows H1 influenza A (HA) to bind sialic acid on cell surfaces, as well as being involved in the post-endocytosis mechanism of cellular infection.; The Baker lab at University of Washington has developed de novo designed miniproteins that bind hemagglutinin, and developed ways to improve their binding through affinity maturation.

Many of the mutations seen in affinity-matured sequences are not directly in the binding interface, and it is unclear how these changes lead to higher affinity.

Understanding this mechanism may help us better computationally design better binders.

We aim to use molecular dynamics simulations to examine ab initio binding pathways for these miniprotein binders, and use enhanced sampling methods to study the unbinding reaction.

Pairing these methods together will provide a robust description of the complete binding reaction for this system.

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miniprotein

A small, engineered protein with a specific function.

Miniproteins are tiny, designed proteins created in the lab. They're used because they're smaller and easier to produce than traditional antibodies, making them promising for new treatments.

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therapeutics

Substances used to treat or prevent disease.

Therapeutics are medications and treatments that aim to cure, manage, or prevent diseases. They can be small molecules, antibodies, or other biological agents.

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infectious disease

A disease caused by a pathogen such as bacteria, virus, or parasite.

Infectious diseases are illnesses spread from one person to another through germs like bacteria and viruses. Examples include the flu, COVID-19, and tuberculosis.

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hemagglutinin

A viral surface protein that allows viruses to bind to host cells.

Hemagglutinin is a protein found on the surface of some viruses. It helps the virus attach to and enter our cells, allowing it to infect us.

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H1 influenza A (HA)

Hemagglutinin subtype of influenza A virus.

H1N1 is a type of influenza virus that causes flu. Hemagglutinin (HA) is a protein on the surface of this virus that helps it attach to our cells.

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sialic acid

A type of sugar molecule found on cell surfaces.

Sialic acid is a common sugar attached to the surface of our cells. Viruses like influenza use it as a docking site to attach and infect us.

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affinity maturation

The process of increasing the binding affinity of an antibody for its target.

Affinity maturation is a technique used to improve antibodies. It involves making small changes in the antibody's structure to make it bind more tightly to its target.

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molecular dynamics simulations

Computer simulations that model the movement and interactions of molecules.

Molecular dynamics simulations are powerful tools used to study how molecules move and interact. They help us understand processes like protein folding and drug binding.

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enhanced sampling methods

Techniques used to accelerate molecular dynamics simulations.

Enhanced sampling methods help us overcome limitations in traditional molecular dynamics simulations. They allow us to study rare events and explore a wider range of possible configurations.