RESEARCH: INFLUENZA
FOLDING PROJECT #12411 PROFILE

Miniproteins are small proteins that can be designed to fight viruses. Researchers are using computer simulations to understand how miniproteins bind to the influenza virus and how changes to their design can improve their effectiveness.

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 engineered proteins smaller than traditional antibodies. They're used in drug development because they can target specific proteins and have fewer side effects. Researchers are exploring their potential to treat diseases like infections.

hemagglutinin

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

Hemagglutinin is a key protein on the surface of the influenza virus. It helps the virus attach to and enter human cells. Scientists are studying hemagglutinin to develop new antiviral drugs and vaccines.

affinity maturation

The process of increasing the binding strength of antibodies.

Affinity maturation is a natural process where the immune system improves the ability of antibodies to bind to their target antigens. Researchers use this process to develop more effective antibodies for therapeutic and diagnostic purposes.

molecular simulation

A computer-based method for simulating molecular behavior.

Molecular simulations use mathematical models to predict how molecules interact with each other. This technique is used to study a wide range of biological processes, from protein folding to drug binding.

expanded ensemble simulation

A type of molecular simulation that explores a wider range of possible states.

Expanded ensemble simulations allow scientists to study systems with large energy barriers. They are particularly useful for investigating complex biological processes that involve multiple conformational states.