RESEARCH: INFLUENZA
FOLDING PROJECT #18482 PROFILE

Miniproteins are small, designed proteins that could be used as new medicines. Scientists want to understand how miniproteins bind to viruses like the flu using computer simulations. They'll use these simulations to see how tiny changes in a miniprotein's design affect its ability to stick to the virus and block infection.

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 engineered proteins that are smaller than traditional antibodies but larger than small molecules. They are being explored as potential treatments for various diseases because they can bind to specific targets in the body.

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Hemagglutinin

A viral protein that allows influenza A to attach to cell surfaces.

Hemagglutinin is a surface protein found on influenza A viruses. It plays a crucial role in the virus's ability to infect cells by binding to sialic acid receptors on the host cell surface.

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Affinity Maturation

Process of improving the binding affinity of a molecule to its target.

Affinity maturation is a technique used to enhance the binding strength of antibodies or other molecules to their desired targets. It involves introducing mutations and selecting for variants with improved binding affinity.

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Molecular Simulation

Computer-based modeling of molecular behavior.

Molecular simulations are computer programs that mimic the movements and interactions of atoms and molecules. They are used to study the structure, dynamics, and properties of biological systems.

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Expanded Ensemble Simulations

A type of molecular simulation that uses multiple independent simulations with different starting conditions.

Expanded ensemble simulations are a powerful computational technique used to study complex systems. They involve running many simulations with slightly different initial conditions, which allows for a more comprehensive exploration of the system's energy landscape.