RESEARCH: INFLUENZA
FOLDING PROJECT #12421 PROFILE

Scientists are using computer simulations to understand how miniproteins (tiny proteins) work and bind to viruses like the flu. This research could lead to new and better treatments for infections.

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 artificially created proteins that are smaller than typical antibodies but larger than small drug molecules. They're designed to bind specific targets in the body, potentially treating diseases like infections.

therapeutic

Relating to the treatment of disease.

Therapeutic refers to anything used to treat or prevent illness. This can include medications, therapies, and lifestyle changes.

hemagglutinin

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

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

affinity maturation

The process of improving the binding strength of antibodies or proteins.

Affinity maturation is a natural process where antibodies become stronger at binding to their target. Scientists can mimic this to create more effective therapies.

molecular simulation

Using computer models to study the behavior of molecules.

Molecular simulations use computer programs to mimic how atoms and molecules interact. This helps scientists understand complex biological processes.