RESEARCH: INFLUENZA
FOLDING PROJECT #12406 PROFILE

Scientists are studying miniproteins, tiny proteins that can block viruses. They want to understand how changes in these miniproteins affect their ability to bind to the flu virus hemagglutinin protein. Using computer simulations, they hope to learn how to design even better miniprotein drugs for fighting 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 engineered proteins smaller than antibodies. They have uses in treating diseases by binding to specific targets in the body.

therapeutics

Substances used to treat or prevent disease.

Therapeutics are medications and treatments used to diagnose, cure, or manage illnesses. This field is focused on developing new drugs and therapies.

hemagglutinin

A viral protein that binds to host cell receptors.

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

affinity maturation

The process of increasing the binding strength of an antibody.

Affinity maturation is a process that enhances the ability of antibodies to bind their target. This is often used in the development of new drugs and therapies.

molecular simulation

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

Molecular simulations use computers to model the movements and interactions of atoms and molecules. This helps researchers understand how drugs work and design new ones.

expanded ensemble simulations

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

Expanded ensemble simulations are used to study complex systems by exploring a larger number of possible configurations. This can help researchers understand how molecules behave under different conditions.