RESEARCH: INFLUENZA
FOLDING PROJECT #12423 PROFILE

Miniproteins are small drugs being designed to fight viruses. This project uses computer simulations to understand how changes to miniproteins affect their ability to bind to a virus protein called hemagglutinin, helping scientists design 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 engineered proteins with therapeutic potential.

Miniproteins are lab-made proteins smaller than traditional antibodies. They're being explored as new drugs because they can be designed to target specific molecules in the body.

biomolecules

Molecules essential to life processes.

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

monoclonal antibodies

Laboratory-produced antibodies that target specific antigens.

Monoclonal antibodies are a type of drug that uses the body's own immune system to fight diseases. They are designed to recognize and bind to specific molecules on cells or viruses.

hemagglutinin

A viral protein that allows influenza A to bind to cells.

Hemagglutinin is a protein found on the surface of the influenza virus. It helps the virus attach to and enter human cells.

affinity maturation

The process of improving antibody binding strength.

Affinity maturation is a natural process by which the immune system improves the ability of antibodies to bind to their targets.

molecular simulation

A computer-based method for studying molecular interactions.

Molecular simulation is a powerful tool that allows scientists to study how molecules interact with each other. This information can be used to design new drugs and materials.