RESEARCH: INFLUENZA
FOLDING PROJECT #12439 PROFILE

This project looks at how miniprotein drugs work against the flu virus. These miniproteins latch onto a protein called hemagglutinin, which helps the virus infect cells. By studying how these miniproteins bind and detach from hemagglutinin using computer simulations, researchers hope to design even better miniprotein drugs in the future.

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 protein designed for therapeutic purposes.

Miniproteins are artificially engineered proteins with a compact size. They possess the potential to act as effective therapeutics due to their ability to target specific biological molecules and pathways.

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therapeutics

Agents used to treat or prevent disease.

Therapeutics encompass a wide range of medical treatments aimed at combating diseases. These include medications, biologics, and other interventions designed to alleviate symptoms, cure illnesses, or improve patient outcomes.

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infectious disease

A disease caused by a pathogen.

Infectious diseases are illnesses resulting from the invasion and multiplication of pathogenic microorganisms within the body. These pathogens can include bacteria, viruses, fungi, and parasites.

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hemagglutinin

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

Hemagglutinin is a crucial viral protein responsible for attaching to and entering host cells. It facilitates the binding of the virus to specific receptors on cell surfaces, enabling the infection process.

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influenza A

A type of virus that causes influenza.

Influenza A is a respiratory virus responsible for seasonal flu outbreaks. It spreads easily through airborne droplets and can cause symptoms such as fever, cough, sore throat, and body aches.

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HA

Hemagglutinin

HA is an acronym commonly used to represent the hemagglutinin protein found on influenza A viruses. This protein plays a vital role in viral attachment and entry into host cells.

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affinity maturation

The process of increasing the binding affinity of an antibody or miniprotein.

Affinity maturation is a biological process where antibodies or other binding molecules undergo changes in their structure to enhance their binding strength. This refinement allows for more effective targeting and neutralization of specific molecules.

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molecular dynamics simulations

Computer simulations of the motion of molecules over time.

Molecular dynamics simulations are powerful computational tools used to model the behavior of atoms and molecules. They provide insights into molecular interactions, conformational changes, and reaction mechanisms.

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enhanced sampling methods

Techniques used to accelerate molecular dynamics simulations.

Enhanced sampling methods are computational strategies employed to overcome limitations in standard molecular dynamics simulations. They allow researchers to explore a wider range of molecular configurations and obtain more comprehensive insights into complex systems.