RESEARCH: INFLUENZA
FOLDING PROJECT #12416 PROFILE

This project explores how miniproteins (small proteins) can be designed to block viruses like flu. Scientists are using computer simulations to understand how changes in the miniprotein's structure affect its ability to bind to the virus, hoping to develop better antiviral treatments.

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 engineered proteins smaller than antibodies but larger than traditional drugs. They are designed to bind specific targets in the body and have shown promise for treating various diseases.

therapeutics

Medicinal agents used to treat diseases.

Therapeutics are medications or treatments used to prevent, diagnose, or cure diseases. This field focuses on developing safe and effective drugs to improve human health.

hemagglutinin

A viral protein that allows influenza viruses to bind to cells.

Hemagglutinin is a crucial protein on the surface of influenza viruses. It helps the virus attach to and enter human cells, facilitating infection. Researchers are actively studying hemagglutinin to develop antiviral drugs and vaccines.

affinity maturation

The process of improving the binding affinity of antibodies.

Affinity maturation is a biological process that enhances the ability of antibodies to bind their target antigens. This process involves mutations in antibody genes, leading to increased binding strength and specificity.

molecular simulation

Computer-based modeling of molecular interactions.

Molecular simulations use computer algorithms to mimic the behavior of molecules and their interactions. This technique is widely used in drug discovery to predict how potential drugs will bind to target proteins.

expanded ensemble simulations

A type of molecular simulation that samples a wider range of conformational states.

Expanded ensemble simulations are advanced computational techniques used to study the dynamic behavior of biomolecules. They overcome limitations of traditional simulations by exploring a broader range of possible conformations.