RESEARCH: INFLUENZA
FOLDING PROJECT #12400 PROFILE

Miniproteins are small, designed proteins that can block viruses. Scientists are using computer simulations to figure out how changes to miniproteins affect their ability to bind to the flu virus. This could help design better treatments for 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 small, engineered proteins used in medicine. They are smaller than traditional antibodies but larger than simple drug molecules. Miniproteins can be designed to bind specific targets in the body, like viruses or disease-causing proteins, offering potential treatments for various illnesses.

Hemagglutinin

A viral protein that allows viruses to attach to and infect cells.

Hemagglutinin is a protein found on the surface of some viruses, including influenza. It acts like a key, binding to specific sugar molecules on cell surfaces to allow the virus to enter and infect the cell. Blocking hemagglutinin can prevent viral infection.

Affinity Maturation

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

Affinity maturation is a technique used in drug development to enhance how well a molecule binds to its intended target. This often involves making small changes to the molecule's structure through repeated rounds of testing and selection, ultimately leading to a more potent and effective therapeutic.

Molecular Simulation

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

Molecular simulations use powerful computers to mimic the interactions between atoms and molecules. This allows researchers to study how drugs bind to their targets, predict the effects of mutations, and design new molecules with desired properties.

Expanded Ensemble Simulation

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

Expanded ensemble simulations are used to study systems with many different energy states. By sampling a broader range of configurations, researchers can obtain more accurate predictions of thermodynamic properties and reaction pathways.