RESEARCH: INFLUENZA
FOLDING PROJECT #12403 PROFILE

Miniproteins are tiny proteins that can be designed to fight viruses like the flu. Scientists want to understand how changing miniproteins affects their ability to bind to the virus, using powerful computer simulations. This will help design better miniprotein drugs in the future.

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 with intermediate size, larger than small molecule drugs but smaller than monoclonal antibodies.

Miniproteins are a class of engineered proteins that are smaller than traditional antibodies but larger than typical drug molecules. They have the potential to be used as therapeutics because they can be designed to bind specifically to target proteins involved in disease processes.

monoclonal antibodies

Laboratory-produced antibodies that target specific antigens.

Monoclonal antibodies are laboratory-made proteins that act like the body's natural antibodies. They are designed to specifically recognize and bind to a particular target, called an antigen. This makes them useful for treating diseases by targeting cancer cells, viruses, or other harmful substances.

hemagglutinin

Viral surface protein that allows influenza A virus to bind to sialic acid on cell surfaces.

Hemagglutinin is a crucial protein found on the surface of influenza viruses. It enables the virus to attach to and enter human cells by binding to a sugar molecule called sialic acid, which is present on cell surfaces. This attachment is the first step in the infection process.

affinity maturation

Process of improving the binding affinity of antibodies through repeated rounds of mutagenesis and selection.

Affinity maturation is a key process in antibody engineering. It involves introducing mutations into an antibody gene, followed by selecting for variants with higher binding affinity to their target antigen. This iterative process can significantly enhance the effectiveness of antibodies as therapeutics.

molecular simulation

Computer-based modeling of molecular interactions and behavior.

Molecular simulations use computational algorithms to mimic the movement and interactions of atoms and molecules. These simulations can be used to study a wide range of biological processes, including protein folding, drug binding, and cellular signaling.

expanded ensemble simulations

Simulation technique that uses multiple parallel simulations with different energy landscapes to explore a wider range of conformational states.

Expanded ensemble simulations are a powerful computational tool used to study complex systems like proteins. They involve running multiple simulations under slightly different conditions, allowing researchers to sample a broader range of possible conformations and better understand the system's behavior.

affinity

Strength of the binding between two molecules.

Affinity refers to the strength with which two molecules, such as a protein and its ligand (e.g., a drug), bind to each other. Higher affinity means stronger binding, making it more likely for the molecules to interact.

mutations

Changes in the DNA sequence that can alter protein structure and function.

Mutations are alterations in the genetic code (DNA) that can lead to changes in the amino acid sequence of proteins. These changes can affect protein structure, function, and interactions with other molecules.