RESEARCH: INFLUENZA
FOLDING PROJECT #12440 PROFILE

This project looks at miniproteins designed to fight the flu virus. They bind to a protein called hemagglutinin, which helps the virus infect cells. Researchers want to understand how these miniproteins work so they can design even better ones in the future. They'll use computer simulations to see how the miniproteins attach and detach from hemagglutinin.

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, engineered proteins with therapeutic potential.

Miniproteins are artificially created proteins designed to be smaller and more effective than traditional antibodies. They have various applications in medicine, including treating infections and diseases.

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therapeutics

Medicines or treatments used to prevent or cure diseases.

Therapeutics are medical interventions aimed at treating or preventing diseases. This can include medications, surgery, or other forms of treatment.

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infectious disease

A disease caused by a pathogenic microorganism.

Infectious diseases are illnesses caused by harmful microorganisms like bacteria, viruses, fungi, or parasites. These pathogens can spread from person to person, animal to person, or through contaminated environments.

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hemagglutinin

A viral protein that allows attachment to host cells.

Hemagglutinin is a key protein found on the surface of influenza viruses. It helps the virus attach to and enter host cells, enabling infection.

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influenza A (HA)

Hemagglutinin subtype of influenza A virus.

Influenza A (HA) refers to a specific type of hemagglutinin protein found on the surface of influenza A viruses. Different subtypes of HA contribute to the variations in influenza strains.

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sialic acid

A type of sugar molecule found on cell surfaces.

Sialic acid is a type of sugar molecule that plays a crucial role in cell recognition and signaling. It is often found attached to proteins and lipids on the surface of cells.

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affinity maturation

The process of improving the binding affinity of an antibody or other biomolecule.

Affinity maturation is a natural process where antibodies evolve to bind more tightly to their target antigens. This occurs through mutations in the antibody genes, resulting in higher-affinity antibodies.

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molecular dynamics simulations

Computer simulations of the movement and interactions of atoms and molecules.

Molecular dynamics simulations are powerful computer models that simulate the behavior of molecules over time. They can be used to study various biological processes, including protein folding, drug binding, and cellular interactions.

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enhanced sampling methods

Techniques used to accelerate the exploration of conformational space in molecular simulations.

Enhanced sampling methods are computational techniques that help researchers overcome limitations in traditional molecular dynamics simulations. They allow for a more thorough exploration of the possible conformations and energy landscapes of molecules.