RESEARCH: INFLUENZA
FOLDING PROJECT #12414 PROFILE

Miniproteins are tiny proteins that can be designed to fight viruses. Scientists are using computer simulations to understand how these miniproteins work and how to make them even better at blocking viral infections like the flu.

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 engineered for therapeutic use.

Miniproteins are a new class of drugs that are smaller than traditional antibodies. They can be designed to bind to specific targets in the body, such as viruses or bacteria, and block their activity. This makes them promising candidates for treating a variety of diseases.

therapeutics

Substances used for treating diseases or medical conditions.

Therapeutics are substances that are used to treat or prevent disease. They can be in the form of drugs, vaccines, or other treatments. The goal of therapeutics is to improve health and quality of life.

hemagglutinin

A viral protein that binds to sialic acid on cell surfaces.

Hemagglutinin is a protein found on the surface of many viruses. It helps the virus attach to and enter host cells. Hemagglutinin is a major target for antiviral drugs.

affinity maturation

The process of improving the binding affinity of an antibody.

Affinity maturation is a process that makes antibodies stronger at recognizing and binding to their target. This process happens naturally in our immune system when we are exposed to a new pathogen.

molecular simulation

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

Molecular simulation is a powerful tool that allows scientists to study how molecules interact with each other. This information can be used to design new drugs, materials, and understand biological processes.