RESEARCH: INFLUENZA
FOLDING PROJECT #12412 PROFILE

This project explores how tiny proteins called miniproteins work to fight viruses. Scientists are using computer simulations to figure out how changes in these miniproteins can make them better at blocking viruses like the flu.

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 with sizes between small molecules and antibodies. They are being researched as potential treatments for various diseases because they can be designed to bind specific targets in the body.

hemagglutinin

A viral protein that allows influenza viruses to attach to and infect host cells.

Hemagglutinin is a key protein found on the surface of influenza viruses. It helps the virus bind to sialic acid receptors on cells, enabling it to enter and infect the host.

affinity maturation

The process of increasing the binding affinity of antibodies or other proteins.

Affinity maturation is a process where the strength of binding between an antibody and its target antigen is improved. This is often achieved through repeated rounds of mutation and selection in laboratory settings.

molecular simulation

Computer-based modeling of molecular behavior.

Molecular simulation uses computer algorithms to simulate the movement and interactions of atoms and molecules. This allows scientists to study the behavior of biological systems at a detailed atomic level.

expanded ensemble simulations

A type of molecular simulation that uses multiple independent simulations to explore a wider range of possible states.

Expanded ensemble simulations are a powerful technique used in computational biology to study systems with complex energy landscapes. By running multiple simulations with different starting conditions, researchers can explore a broader range of possible configurations and obtain more accurate results.