RESEARCH: INFLUENZA
FOLDING PROJECT #18467 PROFILE

This project explores how miniproteins (small drug-like proteins) bind to a flu virus protein called hemagglutinin. Researchers are using computer simulations to understand how changes in the miniprotein's design affect its binding strength. The goal is to improve the design of miniprotein drugs that could treat 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 engineered for therapeutic use.

Miniproteins are a new class of biomolecules designed to be used as drugs. They are smaller than traditional antibodies but larger than small molecules, allowing them to target specific proteins in the body.

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Hemagglutinin

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

Hemagglutinin is a protein found on the surface of influenza viruses. It helps the virus attach to cells in the body, allowing it to infect them.

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influenza A

Influenza virus subtype A

Influenza A is a type of influenza virus that can cause seasonal flu outbreaks. It is characterized by its ability to infect both humans and animals.

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sialic acid

A type of sugar molecule found on the surface of cells.

Sialic acid is a type of sugar molecule that is attached to the surface of many cells in the body. It plays a role in cell signaling and recognition.

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affinity maturation

The process of increasing the binding affinity of an antibody.

Affinity maturation is a process used to improve the ability of antibodies to bind to their target molecules. This can be achieved through genetic mutations that alter the structure of the antibody.

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molecular simulation

A computational method for simulating the behavior of molecules.

Molecular simulations are used to study the interactions between molecules. They can be used to predict how drugs will bind to their targets or how proteins will fold.

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expanded ensemble simulation

A type of molecular simulation that samples a wider range of possible molecular configurations.

Expanded ensemble simulations are used to study systems with many degrees of freedom. They allow researchers to explore a larger portion of the conformational space of a molecule.