RESEARCH: INFLUENZA
FOLDING PROJECT #18447 PROFILE

This project looks at how miniproteins designed to fight the flu virus work. Miniproteins are smaller than antibodies but bigger than regular drugs. Scientists want to understand how changes in these miniproteins make them better at grabbing onto a part of the flu virus called hemagglutinin. Using computer simulations, they'll study how the miniproteins bind and unbind from hemagglutinin to see what makes them so effective.

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 specific functions.

Miniproteins are artificially created proteins that are significantly smaller than traditional antibodies. They have gained attention in drug development due to their ability to target specific molecules and cells effectively. Their small size allows for better tissue penetration and potentially lower side effects compared to larger biologics like antibodies.

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therapeutics

Substances used for treating diseases.

Therapeutics encompass a wide range of medical treatments, including drugs, biologics, and gene therapies. They aim to diagnose, treat, cure, or prevent diseases by targeting specific biological pathways or molecules within the body.

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infectious disease

A disease caused by a pathogen.

Infectious diseases are illnesses that arise from the invasion and multiplication of pathogenic microorganisms, such as bacteria, viruses, fungi, or parasites. These infections can spread through various modes of transmission, including direct contact, airborne particles, contaminated surfaces, or vectors like insects.

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Hemagglutinin

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

Hemagglutinin (HA) is a crucial protein found on the surface of influenza viruses. It plays a vital role in the initial stage of infection by binding to sialic acid receptors present on host cell surfaces. This binding facilitates viral entry into the cells and initiates the replication process.

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influenza A

A type of influenza virus.

Influenza A is a highly contagious respiratory virus responsible for seasonal flu outbreaks worldwide. It is classified into different subtypes based on the surface proteins hemagglutinin (HA) and neuraminidase (NA). Influenza A viruses can cause a range of symptoms, from mild respiratory illness to severe complications like pneumonia.

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HA

Hemagglutinin

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affinity maturation

The process of improving the binding affinity of an antibody.

Affinity maturation is a crucial step in the development of high-potency antibodies. It involves introducing mutations into the variable regions of antibodies to enhance their binding affinity to target antigens. This process often occurs naturally during immune responses, leading to the generation of antibodies with improved specificity and effectiveness.

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molecular dynamics simulations

Computer simulations that model the movement of atoms and molecules.

Molecular dynamics simulations are powerful computational tools used to study the behavior of biological systems at the atomic level. They involve simulating the interactions between atoms and molecules over time, allowing researchers to investigate processes such as protein folding, ligand binding, and cellular dynamics.

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ab initio

From the fundamental principles; without relying on experimental data.

Ab initio methods in computational chemistry refer to theoretical calculations that rely solely on fundamental physical laws and mathematical equations. These calculations aim to predict the properties of molecules and materials without using experimental input or empirical parameters.

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enhanced sampling

Techniques used in molecular dynamics simulations to explore a wider range of conformational states.

Enhanced sampling techniques are employed in molecular dynamics simulations to overcome the limitations of traditional methods. They aim to accelerate the exploration of energetically less accessible regions of the conformational space, enabling researchers to capture rare events and investigate dynamic processes more effectively.