RESEARCH: INFLUENZA
FOLDING PROJECT #18468 PROFILE

Miniproteins are small proteins being developed as new drugs to fight diseases like the flu. Scientists are using powerful computer simulations to understand how miniproteins bind to viruses and how changes in their design can improve their effectiveness.

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 are designed to bind specific targets in the body and are being investigated as potential treatments for various diseases.

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therapeutics

Substances used to treat or prevent diseases.

Therapeutics are medical treatments used to manage and cure illnesses. This can include medications, therapies, and other interventions aimed at restoring health.

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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 allows the virus to attach to and infect host cells by binding to sialic acid, a sugar molecule present on cell surfaces.

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affinity maturation

The process of increasing the binding affinity of antibodies.

Affinity maturation is a biological process where antibodies are genetically modified to enhance their ability to bind to specific targets. This makes them more effective at recognizing and neutralizing pathogens.

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molecular simulation

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

Molecular simulation is a technique used in computational biology to model the interactions between atoms and molecules. This allows scientists to study complex biological processes at an atomic level.

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expanded ensemble

A type of molecular simulation technique.

Expanded ensemble simulations are a powerful computational method used to study complex systems with multiple energy states. By sampling a wider range of configurations, they provide more accurate predictions about the system's behavior.

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mutational effects

The changes in protein function caused by mutations.

Mutational effects refer to the alterations in a protein's structure and function that result from changes in its DNA sequence. These changes can have significant implications for biological processes and disease development.