Computational redesign to change conformation and activity of a redox protein.

Background: NADPH cytochrome P450 oxidoreductase (POR) is very important for metabolic processes in all mammals. Previously we have shown that mutations in this protein can cause serious health problems. While we know that POR supports other proteins to do their jobs, we don't fully understand how changes in POR affect its work with these other proteins.

Rationale: POR has a complicated structure that helps it work with over 50 different proteins. One of its main partners is a group of proteins called cytochrome P450s, which help with many chemical reactions in living things. We want to create new versions of POR that can be used in different applications. By studying these new versions, we hope to learn more about how POR works and how we can control its activity.

Experiments and Aims:

1. Designing New POR Proteins: In Switzerland, we'll use computer programs to design many new versions of POR. We'll test these new versions in human cells and bacteria to see how well they work with cytochrome P450s.
2. Mechanism Studies: With our collaborators, we'll look at POR molecules to see how they move, change shape and interact with partner proteins. This will help us understand how POR works on a very detailed level.

Significance: By understanding how POR works and creating new versions of it, we can improve its use in various applications, like cleaning up oil spills or making new medicines. This research will help us understand the basic principles of how proteins work and how we can design them for specific tasks.