RESEARCH: INFLUENZA
FOLDING PROJECT #12408 PROFILE

This project explores how miniproteins (small proteins) work by studying their binding to a virus protein called hemagglutinin. Using computer simulations, they aim to understand how changes in the miniprotein affect its binding strength and ultimately develop better miniprotein drugs against viruses.

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 drugs that are smaller than traditional antibodies but larger than small molecules. They can be designed to bind specific targets in the body, making them useful for treating a variety of diseases.

biomolecules

Molecules essential for life processes.

Biomolecules are the building blocks of all living organisms. They include proteins, carbohydrates, lipids, and nucleic acids, which perform a wide range of functions in cells.

therapeutics

Agents used to treat diseases.

Therapeutics are substances that are used to prevent, diagnose, or treat disease. They can be administered in various forms, such as pills, injections, or patches.

hemagglutinin

Viral protein that binds to host cell surfaces.

Hemagglutinin is a viral protein found on the surface of influenza viruses. It allows the virus to attach to and enter host cells.

H1

Hemagglutinin subtype 1 influenza A virus.

H1 is a specific type of hemagglutinin protein found on influenza A viruses. It determines the virus's ability to infect certain host cells.

affinity maturation

Process of enhancing antibody binding affinity.

Affinity maturation is a process by which antibodies are modified to bind more strongly to their target antigens. This process is essential for the development of effective vaccines and therapies.

molecular simulation

Computer-based modeling of molecular interactions.

Molecular simulation is a powerful technique that allows researchers to study the behavior of molecules at the atomic level. It can be used to predict how drugs will interact with their targets and to design new therapies.

expanded ensemble simulations

Simulation technique for studying multiple conformational states.

Expanded ensemble simulations are a type of computational method used to study the behavior of molecules in different energy states. This allows researchers to gain a more complete understanding of how molecules function.