RESEARCH: INFLUENZA
FOLDING PROJECT #18480 PROFILE

This project studies miniproteins - tiny proteins designed to fight diseases like the flu. Researchers use computer simulations to see how changes in these miniproteins affect their ability to bind to the flu virus, aiming to create better treatments.

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 engineered for therapeutic use.

Miniproteins are a new class of drug that are smaller than traditional antibodies but larger than small molecules. They can be designed to bind specific targets in the body and have shown promise in treating a variety of diseases.

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hemag glutinin

A viral protein that allows influenza A virus to bind to and infect cells.

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

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affinity maturation

The process of improving the binding affinity of antibodies or other proteins.

Affinity maturation is a natural process used by the immune system to create more effective antibodies. Scientists can also use this process to engineer antibodies with higher affinity for specific targets.

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molecular simulation

A computational method for simulating the behavior of molecules.

Molecular simulation uses mathematical models to predict how molecules will interact with each other. This technique is used to study a wide range of biological processes, including protein folding and drug binding.

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expanded ensemble simulations

A type of molecular simulation that explores a wider range of possible states.

Expanded ensemble simulations are used to study systems with complex energy landscapes. They allow researchers to explore a broader range of conformations and identify the most stable state.