RESEARCH: INFLUENZA
FOLDING PROJECT #18469 PROFILE

This project explores how miniproteins, tiny proteins designed to fight diseases, bind to a target called hemagglutinin found in the flu virus. Scientists are using computer simulations to understand how changes in miniprotein structure affect their ability to bind hemagglutinin and develop better treatments.

Note: This TLDR is a simplication and may not be 100% accurate.

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 antibodies, used in drug development. They can be designed to target specific proteins involved in diseases.

---

Therapeutics

Agents used to treat or prevent disease.

Therapeutics are medicines and treatments that aim to cure, alleviate, or prevent diseases. They can range from small molecules to complex biologics.

---

Infectious Disease

Disease caused by pathogenic microorganisms.

Infectious diseases are illnesses caused by germs like bacteria, viruses, fungi, or parasites. These diseases can spread from person to person, animals to people, or through contaminated environments.

---

Hemagglutinin

Viral protein that binds to sialic acid on host cells.

Hemagglutinin is a protein found on the surface of influenza viruses. It helps the virus attach to and enter host cells by binding to sialic acid molecules.

---

Influenza A (HA)

Subtype of influenza virus.

Influenza A (HA) is a type of influenza virus that can cause seasonal flu epidemics. It is characterized by its hemagglutinin protein.

---

Affinity Maturation

Process of improving binding affinity of a molecule.

Affinity maturation is a technique used to enhance the binding strength of molecules like antibodies or miniproteins to their targets. It involves making small changes in the molecule's structure through mutations.

---

Molecular Simulation

Computer modeling of molecular interactions.

Molecular simulations use computer algorithms to simulate the movement and interactions of atoms and molecules. This allows researchers to study complex biological systems at a detailed level.

---

Expanded Ensemble Simulations

Simulations encompassing multiple energy states.

Expanded ensemble simulations are a type of molecular simulation that considers a wider range of possible energy states for a system. This allows for more accurate predictions of complex biological phenomena.