RESEARCH: INFLUENZA
FOLDING PROJECT #12409 PROFILE

Miniproteins are tiny drugs that can be designed to fight viruses. This project uses computer simulations to understand how changes to these miniproteins affect their ability to bind to the flu virus, helping scientists design even better antiviral treatments.

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.

miniproteins

Small proteins with therapeutic potential.

Miniproteins are a class of biomolecules smaller than antibodies but larger than small molecules. They can be designed to bind specific protein targets, making them promising for treating diseases.

biomolecules

Molecules found in living organisms.

Biomolecules are the building blocks of life. They include proteins, carbohydrates, lipids, and nucleic acids.

therapeutics

Substances used to treat or prevent disease.

Therapeutics are medications or treatments used to manage and cure diseases. They work by targeting specific mechanisms in the body.

infectious disease

A disease caused by a pathogen.

Infectious diseases are illnesses caused by harmful microorganisms like bacteria, viruses, and parasites. They spread through various means, including contact with infected individuals or contaminated objects.

hemagglutinin

A viral protein that allows the virus to bind to cells.

Hemagglutinin is a surface protein found on influenza viruses. It helps the virus attach to and infect host cells by binding to sialic acid receptors on cell surfaces.

influenza A

A type of influenza virus that can infect humans and animals.

Influenza A is a highly contagious respiratory virus that causes seasonal flu outbreaks. It has various subtypes, such as H1N1 and H3N2.

affinity maturation

The process of improving the binding affinity of antibodies.

Affinity maturation is a natural process where antibodies evolve to bind more strongly to their target antigens. It involves mutations in the antibody genes, resulting in increased binding affinity.

molecular simulation

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

Molecular simulations use computational models to predict the movement and interactions of atoms and molecules. They are widely used in drug discovery, materials science, and other fields.

expanded ensemble simulation

A type of molecular simulation that samples a wider range of molecular states.

Expanded ensemble simulations enhance the sampling of conformational space in molecular dynamics. They help explore rare events and provide more accurate predictions of protein folding and binding interactions.