Matt Powner is always searching for his next project. ‘When you don’t know if things are going to work, that’s super exciting,’ he says. ‘That’s what really motivates me to do science.’
At his core, Powner is an organic chemist. Recently, he’s been searching for chemical syntheses that work in water and could have created the first peptides at the origins of life. ‘Understanding the origins of life is obviously a huge problem that implicates lots of different science. And it’s a problem you can really approach with an organic chemist’s skillset,’ he says. ‘But in the lab, we’ve got to break the challenge down into projects that make sense for how we work, so we have to address problems that fit into PhD and postdoctoral timescales.’
Powner’s group came to work on peptide synthesis as complete novices. ‘We wanted to address why biology synthesises peptides in a totally different way to chemists.’ All chemical peptide syntheses essentially work in the same way: incoming amino acids are activated before being incorporated sequentially to grow the polymer from the C terminus, to the N terminus. But biology does the opposite: It starts at the N terminus and makes peptide bonds at the activated C terminus of the growing polymer.
In 2019, Powner’s group reported that aminonitriles can ligate and give rise to peptides under prebiotically plausible conditions. Aminonitriles are widely accepted to be abiotic precursors to amino acids1 – ‘You just hydrolyse them to get the amino acid, in principle. But we considered, “what if we take that intermediate and instead couple that in our reactions? Are aminonitriles predisposed to yield peptides in water?”’
The group found that α-aminonitriles are perfectly set up to be nucleophiles at neutral pH.2 ‘Once it couples, you go from having an aminonitrile, where the amine is donating electrons towards the nitrile, to having an amide nitrile, where the amide is withdrawing electrons from the nitrile. By coupling the aminonitrile into the peptide, you switch the electron donating and electron withdrawing properties of the substrate. Attaching the aminonitrile to the peptide activates it as an electrophile, and then it goes through the next round of activation so you can ligate another aminonitrile,’ he explains. The findings suggest that direct ligation of proteinogenic α-aminonitriles is the simplest prebiotic pathway to peptides.