RESEARCH: INFLUENZA
FOLDING PROJECT #12418 PROFILE

Miniproteins are small proteins designed to fight diseases like the flu. Researchers are using computer simulations to understand how these miniproteins work and how to make them even better at binding to viruses.

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 a class of engineered proteins smaller than traditional antibodies, designed to target specific molecules in the body. They have potential as new drugs for treating various diseases.

Hemagglutinin

A viral protein that allows influenza to bind to and infect cells.

Hemagglutinin is a protein found on the surface of influenza viruses. It helps the virus attach to and enter human cells, allowing it to spread infection. Researchers study hemagglutinin to develop new antiviral drugs and vaccines.

Affinity Maturation

Process of improving the binding strength of antibodies.

Affinity maturation is a technique used to enhance the ability of antibodies to bind to their target molecules. This process involves making specific changes to the antibody's structure, increasing its affinity and effectiveness.

Molecular Simulation

Computer-based modeling of molecular interactions.

Molecular simulation uses computer programs to mimic the behavior of molecules and their interactions. This technique helps researchers understand complex biological processes at a detailed atomic level.

Expanded Ensemble Simulation

Simulation technique used to study complex systems.

Expanded ensemble simulation is a powerful computational method that allows researchers to explore a wider range of possible states and configurations for a system. This is particularly useful for studying complex biological processes with many interacting components.