RESEARCH: INFLUENZA
FOLDING PROJECT #18476 PROFILE

Researchers are using computer simulations to study how tiny proteins called miniproteins bind to a viral protein called hemagglutinin. This could help them design better drugs to fight the flu and other viruses. The project relates to understanding how changes in miniprotein structure affect their ability to bind, and ultimately improve the effectiveness of these potential new 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 of intermediate size, larger than small molecule drugs but smaller than antibodies. They can be engineered to bind specific targets and have potential as therapeutics for various diseases.

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Monoclonal Antibodies

Laboratory-produced antibodies that target specific antigens.

Monoclonal antibodies are laboratory-created antibodies designed to recognize and bind to a specific antigen (a molecule on the surface of cells or pathogens). They are used in various therapies, including cancer treatment and autoimmune disease management.

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Hemagglutinin

Viral protein that binds to sialic acid on cell surfaces.

Hemagglutinin is a viral protein found on the surface of influenza viruses. It plays a crucial role in the initial stages of infection by binding to sialic acid receptors on host cells, allowing the virus to attach and enter.

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Affinity Maturation

Process of improving the binding affinity of a molecule.

Affinity maturation is a process used in biotechnology to enhance the binding strength of molecules, such as antibodies or miniproteins. It involves introducing mutations and selecting variants with higher affinity for their target.

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Molecular Simulation

Computer-based modeling of molecular interactions.

Molecular simulation is a computational technique used to study the behavior of molecules at an atomic level. It involves simulating the movement and interactions of atoms and molecules over time, providing insights into their structure, dynamics, and properties.