RESEARCH: INFLUENZA
FOLDING PROJECT #12422 PROFILE

This project researches miniproteins, tiny drug-like molecules that can block viruses like the flu. Scientists are using computer simulations to see how changing miniprotein designs affects their ability to bind to viral proteins and stop infection. This could lead to better treatments for infectious 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 engineered proteins used for therapeutic purposes.

Miniproteins are designed proteins smaller than antibodies but larger than small molecules. They can bind to specific targets like viruses or receptors in the body and are being researched as potential new treatments for diseases.

therapeutics

Substances used to treat or prevent diseases.

Therapeutics are medications and treatments that aim to cure, alleviate symptoms, or prevent diseases. This field involves extensive research and development of new drugs and therapies.

hemagglutinin

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

Hemagglutinin is a protein found on the surface of influenza viruses. It helps the virus attach to and infect cells by binding to sugar molecules called sialic acid present on cell membranes.

affinity maturation

The process of improving the binding affinity of an antibody or other biomolecule.

Affinity maturation is a biological process where antibodies are improved over time to bind more strongly to their target antigens. This often involves random mutations and selection for higher-affinity antibodies.

molecular simulation

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

Molecular simulations use mathematical models to mimic the movement and interactions of atoms and molecules. This allows researchers to study complex biological processes at the atomic level.

expanded ensemble simulation

A type of molecular simulation that explores multiple energy states simultaneously.

Expanded ensemble simulations are used to study systems with large free energy landscapes. By sampling a wider range of energy states, they can provide more accurate predictions of complex biological phenomena.