RESEARCH: INFLUENZA
FOLDING PROJECT #12419 PROFILE

Researchers are using computer simulations to understand how miniproteins, tiny engineered proteins, bind to a virus protein called hemagglutinin. They want to see how changes to the miniprotein's design affect its binding strength and how this knowledge can help develop better antiviral drugs.

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 that are smaller than antibodies but larger than small molecule drugs. They have the potential to be used as therapeutics for a variety of diseases.

biomolecules

Molecules essential for life processes.

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

therapeutics

Medications used to treat diseases.

Therapeutics are medications that are used to treat or prevent diseases. They work by targeting specific molecules or processes in the body.

infectious disease

Disease caused by pathogens.

Infectious diseases are illnesses caused by microorganisms such as bacteria, viruses, and fungi. They can spread from person to person or through contact with contaminated objects.

hemagglutinin

Viral protein that binds to host cells.

Hemagglutinin is a viral protein that helps viruses attach to and enter host cells. It plays a crucial role in the early stages of infection.

affinity maturation

Process of improving antibody binding.

Affinity maturation is a process where antibodies are selected and modified to bind more strongly to their target antigens. This is often used in the development of new therapeutics.

molecular simulation

Computer-based modeling of molecular behavior.

Molecular simulations use computer algorithms to simulate the movement and interactions of molecules. This allows researchers to study complex biological systems in detail.

expanded ensemble simulation

Simulation technique for studying complex systems.

Expanded ensemble simulations are a type of molecular simulation that can handle large conformational changes in molecules. They are particularly useful for studying proteins and other biomolecules.