RESEARCH: INFLUENZA
FOLDING PROJECT #12420 PROFILE

Miniproteins are small drug-like molecules being designed to fight infections. This project uses computer simulations to understand how miniprotein changes affect their ability to bind to a viral protein called hemagglutinin, which helps the flu virus infect cells. These simulations will help scientists design even better miniprotein drugs.

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 with therapeutic potential.

Miniproteins are a class of biomolecules engineered for drug development. They are smaller than traditional antibodies but larger than small-molecule drugs. Due to their size, they can effectively target specific proteins involved in diseases.

therapeutics

Medicinal substances used to treat or prevent diseases.

Therapeutics encompass a wide range of medicinal agents, including drugs, biologics, and vaccines. Their primary purpose is to diagnose, treat, cure, or prevent diseases.

hemagglutinin

A viral protein that binds to sialic acid on cell surfaces.

Hemagglutinin is a key viral protein found on the surface of influenza viruses. It plays a crucial role in enabling the virus to attach to and infect host cells by binding to sialic acid receptors.

affinity maturation

The process of increasing the binding affinity of an antibody.

Affinity maturation is a critical step in developing highly effective antibodies. It involves introducing mutations into the antibody gene to enhance its ability to bind to its target antigen with greater strength.

molecular simulation

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

Molecular simulations use computational algorithms to mimic the movements and interactions of atoms and molecules. This technique allows researchers to study complex biological processes at an atomic level.