RESEARCH: INFLUENZA
FOLDING PROJECT #12407 PROFILE

Researchers are using computer simulations to understand how miniproteins (tiny disease-fighting proteins) bind to viruses like the flu. They want to see how changes to miniprotein design affect their ability to stop viruses, which could lead to better treatments.

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 engineered proteins smaller than traditional antibodies. They can be designed to bind specific targets in the body, like viruses or disease-causing proteins, making them promising new treatments.

Hemagglutinin

A viral protein that allows influenza to attach to cells.

Hemagglutinin is a crucial protein found on the surface of influenza viruses. It binds to sugar molecules called sialic acids on human cells, enabling the virus to attach and enter our bodies.

Affinity Maturation

Process of improving a protein's binding affinity.

Affinity maturation is a technique used to enhance the ability of proteins, like antibodies or miniproteins, to bind their target molecules more strongly. This process often involves making small changes to the protein's structure through mutations.

Molecular Simulation

Computer-based method to study molecular behavior.

Molecular simulations use mathematical models and algorithms to simulate the movements and interactions of atoms and molecules. This allows scientists to study complex biological processes at the atomic level.