RESEARCH: INFLUENZA
FOLDING PROJECT #18448 PROFILE

This project looks at miniproteins that block flu viruses. Scientists want to understand how these miniproteins work by using computer simulations to see how they bind to the virus and then come apart. This could help us 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 engineered for specific functions.

Miniproteins are artificially created proteins that are much smaller than traditional antibodies. They're designed to have specific biological activities, like binding to other molecules or acting as enzymes. Their small size makes them easier to produce and potentially more effective in treating diseases.

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therapeutic

A substance used to treat or prevent disease.

Therapeutics are medications or treatments designed to address medical conditions. They can range from small molecules that target specific proteins to complex biologics like antibodies.

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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. They spread from person to person or through contaminated environments and can range in severity from mild to life-threatening.

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hemagglutinin

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

Hemagglutinin is a key protein found on the surface of influenza viruses. It allows the virus to attach to and enter host cells by binding to sialic acid molecules present on cell surfaces.

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influenza A

A type of influenza virus that can cause seasonal flu epidemics.

Influenza A is a highly contagious respiratory virus responsible for widespread seasonal outbreaks. It's classified into subtypes based on two surface proteins: hemagglutinin and neuraminidase.

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binding

The interaction between two molecules.

Binding refers to the specific interaction between two molecules, often involving weak forces like hydrogen bonds or electrostatic attractions. In biological systems, binding plays a crucial role in processes like enzyme catalysis, signal transduction, and drug action.

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affinity maturation

The process of increasing the binding affinity of an antibody.

Affinity maturation is a biological process that enhances the strength of antibody binding to its target antigen. It involves random mutations in the genes encoding antibodies, followed by selection for variants with higher affinity.

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molecular dynamics simulations

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

Molecular dynamics simulations are computer-based methods that allow scientists to study the behavior of molecules over time. They involve simulating the movements and interactions of atoms within a molecule, providing insights into its structure, function, and dynamics.

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enhanced sampling

Methods used to accelerate molecular simulations.

Enhanced sampling techniques are employed in computational biology to overcome limitations in traditional molecular simulations. They aim to explore a wider range of possible configurations and events, providing more complete and accurate representations of complex biomolecular systems.