RESEARCH: INFLUENZA
FOLDING PROJECT #12459 PROFILE

This project explores how miniproteins designed to fight flu viruses bind to the virus's hemagglutinin protein. By using computer simulations, researchers hope to understand how changes in the miniprotein's structure lead to stronger binding. This knowledge can help design even better miniprotein drugs against infectious diseases.

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 defined function.

Miniproteins are tiny, designed proteins used in drug development. They're smaller than traditional antibodies but can still target specific molecules in the body. Miniproteins offer advantages like faster production and improved tissue penetration.

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Therapeutics

Substances used for the treatment or prevention of disease.

Therapeutics encompass various medical treatments aimed at preventing, diagnosing, or treating diseases. This includes drugs, biologics, and other therapies.

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Infectious Disease

A disease caused by a pathogen.

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

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Hemagglutinin

A viral glycoprotein that binds to sialic acid on host cells.

Hemagglutinin is a protein found on the surface of some viruses, like influenza. It helps the virus attach to and enter host cells by binding to sugar molecules called sialic acid.

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Influenza A

A type of influenza virus that can cause seasonal epidemics.

Influenza A is a contagious respiratory illness caused by the influenza A virus. It spreads easily through coughs and sneezes, leading to symptoms like fever, cough, sore throat, and body aches.

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HA

Hemagglutinin

HA stands for Hemagglutinin, a protein found on the surface of influenza A virus. It plays a crucial role in viral attachment and entry into host cells.

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Sialic Acid

A type of sugar molecule found on cell surfaces.

Sialic acid is a complex sugar that plays various roles in biological processes. It's often found on the surface of cells, acting as a recognition site for viruses and other molecules.

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Affinity Maturation

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

Affinity maturation is a technique used to enhance the binding strength between antibodies and their target antigens. It involves introducing mutations into the antibody genes, selecting for variants with higher affinity.

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Molecular Dynamics Simulations

Computer simulations of the movement of atoms and molecules.

Molecular dynamics simulations are computer programs that model the behavior of molecules over time. They can be used to study various biological processes, such as protein folding and drug binding.

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Enhanced Sampling Methods

Techniques used to increase the sampling efficiency of molecular dynamics simulations.

Enhanced sampling methods are computational strategies employed in molecular dynamics simulations to overcome limitations in exploring complex energy landscapes. They aim to sample rare events and improve the accuracy of simulation results.