RESEARCH: INFLUENZA
FOLDING PROJECT #12405 PROFILE

Miniproteins are small proteins that can be designed to fight viruses. This project uses computer simulations to study how changes to miniproteins affect their ability to bind to a virus protein called hemagglutinin. The goal is to better understand how miniproteins work and improve the design of new antiviral drugs.

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 novel class of therapeutics. They are smaller than traditional antibodies but larger than small molecule drugs. Their size allows them to bind specific protein targets with high affinity, making them promising candidates for treating various diseases.

hemagglutinin

Viral protein responsible for binding to host cells.

Hemagglutinin is a surface protein found on influenza A viruses. It plays a crucial role in the virus's ability to infect host cells by binding to sialic acid receptors on cell surfaces.

affinity maturation

Process of enhancing antibody binding affinity.

Affinity maturation is a process used to improve the binding strength of antibodies. This involves introducing mutations into the antibody gene sequence, which can lead to increased binding affinity for the target antigen.

molecular simulation

Computer-based model of molecular interactions.

Molecular simulations use computer algorithms to simulate the behavior of molecules. This technique is widely used in drug discovery and development to predict how molecules interact with each other and with biological targets.

expanded ensemble simulation

Type of molecular simulation that uses multiple sets of parameters.

Expanded ensemble simulations are a specialized type of molecular dynamics simulation that use multiple sets of simulation parameters. This allows for more accurate and comprehensive exploration of complex systems.