RESEARCH: INFLUENZA
FOLDING PROJECT #18479 PROFILE

Researchers are using computer simulations to understand how miniproteins, small engineered proteins, bind to a viral protein called hemagglutinin. They want to see how changing the miniprotein's structure affects its binding strength. This project could lead to better design of miniprotein drugs to fight viruses like influenza.

Note: This TLDR is a simplication and may not be 100% accurate.

Designed miniproteins are a class of biomolecules with intermediate sizes—larger than small-molecule drugs, but smaller than monoclonal antibodies.

Miniproteins can be computationally designed to tightly bind protein targets for use as potential therapeutics, a promising new avenue for treating 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 improved their binding through affinity maturation (Chevalier et al.

2017).

Many of the mutations seen in affinity-matured sequences are not found in the binding interface, and it remains an open question how these changes lead to higher affinity.

Furthermore, many of the computational predictions of how single-point mutations affect binding deviate significantly from the experimentally determined values. Could all-atom molecular simulation approaches achieve more accurate predictions? In this set of simulations, we aim to use massively parallel expanded ensemble simulations to predict mutational effects on affinities to hemagglutinin.

By pairing these simulations with other simulations aimed at modeling the binding reactions of these miniproteins to hemagglutinin, we aim to have a relatively complete picture of a miniprotein-target binding reaction and how mutations affect it.

These studies are a large-scale investigation on how miniprotein binding reactions work in atomic detail, towards a better understanding of computational design and modulation of miniprotein therapeutics.

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miniproteins

Small proteins designed for therapeutic use.

Miniproteins are engineered proteins smaller than antibodies, used in drug development to target specific proteins. They hold promise for treating diseases by binding to and modulating the activity of disease-causing proteins.

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biomolecules

Molecules found in living organisms.

Biomolecules are the building blocks of life. They include proteins, carbohydrates, lipids, and nucleic acids, and play crucial roles in biological processes like metabolism, growth, and reproduction.

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Monoclonal Antibodies

Laboratory-produced antibodies that target a specific antigen.

Monoclonal antibodies are engineered immune system proteins designed to recognize and bind to specific targets, like cancer cells or viruses. They are used in therapies to treat various diseases by blocking harmful substances or stimulating the immune system.

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Hemagglutinin

A viral protein that allows viruses to attach to host cells.

Hemagglutinin is a surface protein found on many viruses, including influenza. It helps the virus bind to and enter host cells by recognizing specific sugar molecules on cell surfaces.

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H1 Influenza A

A type of influenza virus.

H1N1 is a subtype of influenza A virus that can cause seasonal flu epidemics. It's characterized by its hemagglutinin protein (H1) and neuraminidase protein (N1). Vaccines are available to protect against H1N1 infection.

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Affinity Maturation

The process of improving the binding affinity of a molecule to its target.

Affinity maturation is a technique used in drug development to enhance the effectiveness of molecules that bind to specific targets. It involves introducing mutations into the molecule's structure to increase its strength and specificity of binding.