RESEARCH: INFLUENZA
FOLDING PROJECT #12417 PROFILE

Miniproteins are small proteins being developed as new drugs. This project uses computer simulations to understand how miniproteins bind to a virus protein called hemagglutinin. By studying how changes in the miniprotein affect its binding, researchers hope to design better miniprotein drugs against viruses like influenza.

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 to target specific biological molecules.

Miniproteins are engineered proteins that are smaller than traditional antibodies but larger than small-molecule drugs. They have potential as therapeutics because they can bind tightly to specific targets in the body, like viruses or disease-causing proteins.

Hemagglutinin

A viral protein that allows influenza A virus to attach to and infect host cells.

Hemagglutinin is a key protein on the surface of influenza viruses. It helps the virus bind to sialic acid receptors on human cells, enabling it to enter and infect them. This makes it a prime target for antiviral drugs.

Affinity Maturation

A process of improving the binding affinity of an antibody or protein to its target.

Affinity maturation is a technique used to enhance the effectiveness of antibodies. It involves introducing mutations into the antibody gene and selecting for variants that bind more strongly to their intended target.

Molecular Simulation

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

Molecular simulations use mathematical models to recreate the interactions between atoms and molecules. They are valuable tools for studying protein folding, drug design, and other biological processes.