RESEARCH: INFLUENZA
FOLDING PROJECT #18478 PROFILE

This project studies miniproteins – tiny proteins that can be designed to block viruses. They're looking at how changes in the miniprotein affect its ability to bind to a flu virus protein, using powerful computer simulations. This could help us design better antiviral drugs.

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 purposes.

Miniproteins are artificially created proteins with sizes between small molecules and antibodies. They have the potential to be highly effective drugs because they can be specifically designed to target certain proteins in the body.

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Hemagglutinin

A viral protein that allows influenza A to attach to and infect cells.

Hemagglutinin is a key protein found on the surface of influenza A viruses. It helps the virus bind to sialic acid receptors on cell surfaces, allowing it to enter and infect cells. Hemagglutinin is a target for antiviral drugs and vaccines.

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Monoclonal Antibodies

Lab-produced antibodies that target specific antigens.

Monoclonal antibodies are engineered immune system proteins designed to bind to specific targets (antigens) in the body. They are used as therapeutics to treat a wide range of diseases, including cancer, autoimmune disorders, and infectious diseases.

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Affinity Maturation

A process of improving the binding affinity of a protein to its target.

Affinity maturation is a technique used in drug development to enhance the binding strength of a protein (often an antibody or miniprotein) to its desired target. This process involves making small changes to the protein's structure, which can result in significantly improved binding affinity and therapeutic efficacy.

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Molecular Simulation

A computer-based method for modeling the behavior of molecules.

Molecular simulations use mathematical models to simulate the movements and interactions of atoms and molecules. These simulations can be used to study a wide range of biological processes, including protein folding, drug binding, and enzyme catalysis.