RESEARCH: INFLUENZA
FOLDING PROJECT #12456 PROFILE

Miniproteins are being designed to fight the flu by blocking a key viral protein called hemagglutinin. Scientists want to understand how these miniproteins work so they can design even better ones. They'll use computer simulations to track how the miniproteins bind and unbind from hemagglutinin, giving us a detailed picture of this important interaction.

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

Small proteins engineered for specific functions.

Miniproteins are artificially created proteins that are smaller than traditional antibodies. They're designed to perform specific tasks, like binding to viruses or other targets. Miniproteins offer advantages over larger proteins and drugs because they are easier to manufacture and can be more effective at reaching their targets.

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therapeutics

Medicinal treatments designed to prevent or cure diseases.

Therapeutics refer to medications and other treatments used to manage and treat illnesses. They can work in various ways, such as blocking harmful substances, stimulating the immune system, or replacing missing substances.

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infectious disease

Illness caused by pathogenic microorganisms.

Infectious diseases are illnesses caused by harmful microbes like bacteria, viruses, fungi, or parasites. These pathogens can spread from person to person, through contaminated food or water, or via insect bites. Infectious diseases often present with symptoms such as fever, cough, fatigue, and body aches.

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hemagglutinin

Viral protein that binds to sialic acid on host cells.

Hemagglutinin is a crucial protein found on the surface of influenza viruses. It allows the virus to attach to and enter human cells by binding to a sugar molecule called sialic acid, which is present on cell surfaces.

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Influenza A (HA)

Subtype of influenza virus characterized by the hemagglutinin protein (HA).

Influenza A (HA) is a subtype of the influenza virus. It's known for causing seasonal flu epidemics and pandemics. The 'HA' refers to the hemagglutinin protein, which plays a key role in the virus's ability to infect human cells.

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molecular dynamics

Computational method for simulating the movement of atoms and molecules.

Molecular dynamics simulations are computer models used to study how atoms and molecules interact over time. They allow scientists to understand how proteins fold, how drugs bind to their targets, and how chemical reactions occur at the molecular level.

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affinity maturation

Process of improving the binding affinity of antibodies through mutations.

Affinity maturation is a crucial process in antibody development. It involves introducing mutations into an antibody's structure to enhance its ability to bind to its target antigen. This often leads to more effective therapeutic antibodies.