RESEARCH: INFLUENZA
FOLDING PROJECT #18471 PROFILE

Miniproteins are tiny proteins that can be designed to fight diseases. Scientists want to understand how changes in miniprotein design affect their ability to bind to viral proteins, like those found in the flu. They're using computer simulations to see how different miniprotein designs work at an atomic level. This could lead to better treatments for infectious diseases.

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 engineered proteins with therapeutic potential.

Miniproteins are artificially created proteins smaller than antibodies. They are being explored as drugs due to their ability to bind specific targets in the body. Researchers can design miniproteins to target diseases like infections.

Hemagglutinin

A viral protein that allows influenza to bind to cells.

Hemagglutinin is a crucial protein found on the surface of influenza viruses. It enables the virus to attach to and infect human cells by binding to sialic acid molecules on cell surfaces. This process is essential for the virus to replicate and spread.

Affinity Maturation

The process of improving the binding strength of a protein to its target.

Affinity maturation is a technique used in biotechnology to enhance the effectiveness of proteins like antibodies. It involves making small changes to the protein's structure to increase its ability to bind tightly to its desired target molecule, often resulting in improved therapeutic outcomes.

Molecular Simulation

Computer-based modeling of molecular interactions.

Molecular simulations use computer programs to recreate the movements and interactions of atoms and molecules. This allows scientists to study how proteins bind to each other or to drugs, how cells function, and other complex biological processes.