RESEARCH: INFLUENZA
FOLDING PROJECT #18473 PROFILE

Miniproteins are small proteins that can be designed to fight viruses like the flu. Scientists want to use computer simulations to understand how changes to miniprotein design affect their ability to bind to the flu virus and block its spread. This could lead to better flu treatments in the future.

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 artificially created proteins smaller than antibodies but larger than traditional drugs. They are being explored as potential treatments for various diseases because they can be precisely engineered to target specific molecules in the body.

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Hemagglutinin

A viral protein that allows influenza to bind to cells.

Hemagglutinin is a surface protein found on the influenza virus. It plays a crucial role in the virus's ability to infect host cells by binding to sialic acid receptors on cell surfaces.

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Affinity Maturation

Process of improving the binding strength of antibodies or other proteins.

Affinity maturation is a technique used to enhance the binding ability of antibodies or proteins. It involves introducing random mutations and selecting those with improved affinity for their target.

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Molecular Simulation

Computer-based modeling of molecular interactions.

Molecular simulation involves using computer algorithms to mimic the behavior of molecules. This technique allows researchers to study how molecules interact and evolve over time, providing insights into biological processes.

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Expanded Ensemble Simulation

Simulation technique that samples multiple energy states simultaneously.

Expanded ensemble simulation is a computational method used to study systems with multiple energy states. It allows researchers to explore a wider range of possibilities and improve the accuracy of their predictions.