RESEARCH: INFLUENZA
FOLDING PROJECT #18461 PROFILE

Miniproteins are tiny proteins that can fight diseases. Scientists are using computer simulations to understand how miniproteins bind to viruses, like the flu. They want to see if these simulations can predict how changes to miniproteins affect their ability to fight viruses. This will help create better miniprotein drugs 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 with therapeutic potential.

Miniproteins are engineered proteins smaller than antibodies but larger than small molecules. They have applications in treating diseases by binding to specific targets in the body.

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Hemagglutinin

A viral protein that allows influenza to attach to cells.

Hemagglutinin is a protein found on the surface of influenza viruses. It helps the virus attach to and enter human cells, allowing it to infect and spread.

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affinity maturation

Process of enhancing antibody binding to target.

Affinity maturation is a process used to improve the binding strength of antibodies to their targets. This is often done through genetic engineering techniques that introduce mutations into the antibody gene.

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molecular simulation

Computer-based modeling of molecular interactions.

Molecular simulations use computer algorithms to model the movement and interactions of atoms and molecules. This allows scientists to study complex biological processes at a detailed level.

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expanded ensemble simulations

Advanced simulation technique for studying complex systems.

Expanded ensemble simulations are a type of computational modeling that uses multiple sets of simulation parameters to explore a wider range of possible system states. This allows scientists to study complex systems with greater accuracy and efficiency.