RESEARCH: INFLUENZA
FOLDING PROJECT #12401 PROFILE

Miniproteins are small, engineered proteins that can fight diseases like the flu. This project uses computer simulations to understand how miniproteins bind to flu viruses and how tiny changes in their design affect their effectiveness. The goal is to improve the design of these miniprotein 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 designed for therapeutic use.

Miniproteins are small engineered proteins being developed as new drugs. They are smaller than traditional antibodies but larger than small molecules, allowing for precise targeting of disease-causing proteins.

therapeutics

Agents used to treat or prevent diseases.

Therapeutics are medications and other treatments used to cure, prevent, or manage diseases. They can include drugs, vaccines, and therapies.

hemagglutinin

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

Hemagglutinin is a protein found on the surface of influenza viruses. It helps the virus attach to and enter human cells by binding to sugar molecules called sialic acid.

affinity maturation

The process of increasing the binding affinity of antibodies or other molecules.

Affinity maturation is a process where antibodies become more effective at binding to their target antigens. This happens through mutations in the antibody genes, making them stronger binders.

molecular simulation

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

Molecular simulations use computer algorithms to mimic how atoms and molecules interact. This allows scientists to study chemical reactions, protein folding, and other biological processes.