RESEARCH: INFLUENZA
FOLDING PROJECT #12413 PROFILE

This project investigates how miniproteins, small drug-like molecules, bind to viruses like influenza. Researchers are using computer simulations to understand how tiny changes in the miniprotein's structure affect its ability to latch onto the virus and potentially block infection. These findings could lead to better design of miniprotein drugs for treating viral diseases.

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 new class of medication made from small proteins. They can be designed to bind specifically to target proteins in the body, potentially treating diseases like infections.

biomolecules

Molecules that are essential to life and often found in living organisms.

Biomolecules are the building blocks of all living things. They include proteins, carbohydrates, lipids, and nucleic acids.

monoclonal antibodies

Laboratory-made proteins that mimic the immune system's ability to fight off specific targets.

Monoclonal antibodies are a type of medication used to treat various diseases. They work by targeting and destroying specific cells or molecules in the body.

hemagglutinin

A viral protein that allows viruses to attach to host cells.

Hemagglutinin is a protein found on the surface of certain viruses, like influenza. It helps the virus stick to and enter human cells.

H1 influenza A

A subtype of the influenza virus.

H1 influenza A is a common type of flu virus that can cause seasonal illness.

sialic acid

A type of sugar molecule found on the surface of cells.

Sialic acid is a sugar that plays a role in cell recognition and communication.

affinity maturation

The process of improving the binding affinity of antibodies or other molecules.

Affinity maturation is a process used to make antibodies stronger and more effective at targeting their specific targets.

molecular simulation

The use of computer models to simulate the behavior of molecules.

Molecular simulations are used to study how molecules interact and behave. This can help researchers understand how drugs work and design new ones.

expanded ensemble simulation

A type of molecular simulation that uses multiple simulations to explore a wider range of possible energy states.

Expanded ensemble simulations are used to study complex systems and improve the accuracy of predictions.