RESEARCH: INFLUENZA
FOLDING PROJECT #18472 PROFILE

Miniproteins are tiny drugs being designed to fight infections. Scientists are using computer simulations to understand how miniproteins bind to viruses and improve their effectiveness. This research could lead to better treatments for diseases like the flu.

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 but larger than small molecules. They have potential as therapeutics because they can be designed to bind specific targets in the body.

---

Monoclonal Antibodies

Laboratory-produced antibodies that target a specific antigen.

Monoclonal antibodies are a type of protein produced in labs to recognize and bind to specific molecules (antigens). They are used in treatments for various diseases like cancer and autoimmune disorders.

---

Hemagglutinin

A viral surface 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 human cells by binding to sialic acid molecules on cell surfaces.

---

Affinity Maturation

A process of improving the binding affinity of a protein.

Affinity maturation is a technique used to enhance the ability of proteins, particularly antibodies or miniproteins, to bind their target molecules. This involves introducing mutations and selecting for variants with stronger binding.

---

Molecular Simulation

A computer-based method for modeling molecular interactions.

Molecular simulation uses computer programs to mimic the movement and behavior of atoms and molecules. This allows researchers to study how biological systems work at a detailed level.