RESEARCH: INFLUENZA
FOLDING PROJECT #18463 PROFILE

This project studies miniproteins, tiny proteins designed to fight diseases like the flu. They look at how changes in these miniproteins affect their ability to bind to a virus protein called hemagglutinin. Using powerful computer simulations, they hope to understand how miniproteins work and improve their design for 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 with therapeutic potential.

Miniproteins are designed proteins smaller than antibodies but larger than traditional drugs. They can be engineered to bind specific targets like viruses or bacteria, making them promising treatments for diseases.

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monoclonal antibodies

Laboratory-produced antibodies that target a single antigen.

Monoclonal antibodies are lab-made proteins designed to recognize and attack specific targets in the body. They're used to treat various diseases, including cancer and autoimmune disorders.

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hemagglutinin

A viral protein that binds to sialic acid on cell surfaces.

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 us.

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affinity maturation

The process of increasing the binding affinity of an antibody.

Affinity maturation is like fine-tuning an antibody's ability to stick to its target. Researchers use this process to create antibodies that are more effective at fighting diseases.

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molecular simulation

Computer modeling of molecular interactions.

Molecular simulations use computer programs to mimic how molecules interact with each other. This helps researchers understand complex biological processes and design new drugs.

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expanded ensemble simulation

A type of molecular simulation that explores multiple energy landscapes.

Expanded ensemble simulations are powerful tools for studying complex systems. They allow researchers to explore a wider range of possible outcomes and gain deeper insights into how molecules behave.