RESEARCH: INFLUENZA
FOLDING PROJECT #12415 PROFILE

Miniproteins are small, engineered proteins that can fight diseases. Scientists want to understand how miniproteins bind to viruses, like the flu. They're using computer simulations to study how changes in miniproteins affect their binding strength and aim to improve these tiny 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 engineered proteins that are smaller than traditional antibodies. They can be designed to bind specific targets in the body, making them useful for treating diseases. Researchers are exploring their potential in areas like infectious disease treatment.

Hemagglutinin

A viral protein that binds to cell surfaces, enabling the virus to infect cells.

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

Affinity Maturation

The process of enhancing the binding strength of antibodies or proteins to their targets.

Affinity maturation is a technique used to improve the effectiveness of antibodies or proteins that bind to specific targets. It involves making small changes to the protein's structure, which can increase its ability to attach and interact with its target.

Molecular Simulation

Computer-based modeling of molecular interactions and processes.

Molecular simulation uses computer algorithms to simulate the behavior of molecules at an atomic level. This allows researchers to study how molecules interact, which is essential for understanding biological processes and designing new drugs.

Expanded Ensemble Simulations

A type of molecular simulation that samples multiple energy states simultaneously.

Expanded ensemble simulations are a powerful technique used in computational biology to study complex systems. By sampling multiple energy states at once, they can provide a more complete and accurate picture of the system's behavior.