RESEARCH: INFLUENZA
FOLDING PROJECT #12402 PROFILE

This project studies how miniproteins (tiny disease-fighting proteins) bind to flu virus proteins. Scientists use computer simulations to see how changes in the miniprotein's structure affect its ability to block the virus. This helps design better miniprotein drugs for treating 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 proteins with therapeutic potential.

Miniproteins are a new class of biomolecules used in medicine. They are smaller than antibodies but larger than regular drugs. Scientists are exploring their use to treat diseases like infections.

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 infect cells in the body.

affinity maturation

The process of increasing the binding strength of an antibody.

Affinity maturation is a process used to improve the effectiveness of antibodies. It involves making small changes to the antibody's structure to make it bind more tightly to its target.

molecular simulation

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

Molecular simulations use computers to model how molecules interact with each other. This helps researchers understand complex biological processes.

expanded ensemble simulations

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

Expanded ensemble simulations are used to study complex systems by running many simulations with slightly different parameters. This helps to overcome limitations of single simulations.