RESEARCH: INFLUENZA
FOLDING PROJECT #12410 PROFILE

This project studies tiny proteins called miniproteins designed to block flu viruses. Scientists use computer simulations and experiments to see how changes in the miniprotein's structure affect its ability to bind to the flu virus, aiming to improve their effectiveness as potential 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, designed to target specific molecules in the body for medical treatment. They offer advantages over traditional drugs due to their high specificity and ability to be easily modified.

therapeutics

Substances used for treating diseases.

Therapeutics are medications and treatments designed to prevent, diagnose, or cure diseases. They can range from small molecules to complex biological agents like antibodies.

hemagglutinin

Viral protein that binds to sialic acid on cell surfaces.

Hemagglutinin is a surface protein found on influenza viruses. It plays a crucial role in the virus's ability to infect cells by binding to sugar molecules (sialic acid) present on cell surfaces.

affinity maturation

Process of increasing the binding affinity of antibodies.

Affinity maturation is a natural process where antibodies are refined over time to bind their target antigens more effectively. This involves mutations that enhance the antibody's ability to recognize and bind its specific target.

molecular simulation

Computer-based modeling of molecular interactions.

Molecular simulations use computer algorithms to model the behavior of molecules and their interactions. These simulations can be used to study a wide range of biological processes, from protein folding to drug design.

expanded ensemble simulation

Advanced simulation technique for studying complex systems.

Expanded ensemble simulations are a powerful computational tool used to study complex biological systems that involve multiple energy states. These simulations allow researchers to explore a wider range of possible configurations and obtain more accurate predictions.