RESEARCH: INFLUENZA
FOLDING PROJECT #18474 PROFILE

Miniproteins are tiny proteins being designed as new medicines. This project uses computer simulations to understand how miniproteins bind to a viral protein, and how changing the miniprotein's design can improve its binding. This could lead to better treatments for diseases like the flu.

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, engineered proteins with therapeutic potential.

Miniproteins are a new class of drugs that are smaller than traditional antibodies. They can be designed to bind to specific targets in the body, making them useful for treating a variety of diseases.

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therapeutics

Substances used for treating diseases or medical conditions.

Therapeutics are medications or treatments used to prevent, diagnose, or cure diseases. They can include drugs, biologics, and other therapies.

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hemagglutinin

A viral protein that binds to sialic acid on host cells.

Hemagglutinin is a protein found on the surface of influenza viruses. It helps the virus attach to and enter human cells. Scientists are studying hemagglutinin to develop new antiviral drugs.

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affinity maturation

The process of increasing the binding affinity of an antibody.

Affinity maturation is a process that improves the ability of antibodies to bind to their target antigens. This process is important for developing effective vaccines and immunotherapies.

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molecular simulation

A computational method for modeling the behavior of molecules.

Molecular simulations are computer programs that simulate the movements and interactions of atoms and molecules. This technique is used to study various biological processes and design new drugs.