RESEARCH: INFLUENZA
FOLDING PROJECT #12404 PROFILE

This project explores how miniproteins, tiny engineered proteins, bind to viral targets like the H1 influenza A virus. Scientists are using computer simulations to understand how changes in miniprotein design affect their ability to block the virus's grip on cells. This research could lead to better miniprotein-based drugs for treating infections.

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 are being explored as a new type of drug due to their ability to bind specific targets in the body.

Hemagglutinin

A viral protein that helps the virus attach to and infect cells.

Hemagglutinin is a protein found on the surface of influenza viruses. It binds to sialic acid receptors on cells, allowing the virus to attach and enter the cell.

affinity maturation

The process of improving the binding affinity of a molecule to its target.

Affinity maturation is a technique used to enhance the ability of a protein or antibody to bind to its specific target. This is often done by introducing mutations and selecting for those with higher binding strength.

molecular simulation

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

Molecular simulations use mathematical models to simulate the interactions between atoms and molecules. This allows researchers to study how drugs interact with their targets and predict their effectiveness.

expanded ensemble simulation

A type of molecular simulation that samples a wider range of possible conformations.

Expanded ensemble simulations are used to study systems with complex energy landscapes. By sampling a broader range of conformations, researchers can gain a more complete understanding of the system's behavior.