The Legos of Life: Primordial Proteins Unveiled

The structure of four organic building blocks, termed the “Legos of Life”, have been decoded by scientists at Rutgers University. These structures are a glimpse of what primordial proteins may have looked like billions of years ago, and yet may have ramifications for modern-day industry. 

The study’s authors, led by Associate Professor Vikas Nanda, wanted to look back through time to see what proteins may have looked like near the origin of life.

“One fundamental use for proteins early on was to take advantage of abundant electrochemical energy in the geosphere,” Nanda says. “As an example - in deep sea hydrothermal events, the contents of the vents are very reducing (electron rich) as compared to the ocean which is more oxidizing.  As a result, there is an electrical potential - a voltage - that occurs at the site of such vents.  Similar voltages exist between the ocean and the atmosphere, and at other interfaces.  We and others believe the earliest proteins used this potential to catalyze reactions critical for life.” 

Walking Proteins Backwards Through Time 

Nanda and colleagues began the search for these ancient proteins using 3D data from the vast RCSB Protein Data Bank, a global archive that contains the 3D structures of nearly 140,000 biological macromolecules, rendered in atomic-level detail. "We don't have a fossil record of what proteins looked like 4 billion years ago, so we have to take what we have today and start walking backwards, trying to imagine what these proteins looked like," said Nanda, of the Department of Biochemistry and Molecular Biology at Rutgers' Robert Wood Johnson Medical School. 

Modern proteins largely make use of metal centers in protein structures, and the team used this as a starting point to narrow down the RCSB’s structural trove. “We identified all metal binding proteins in the PDB and then separated the coordinates of atoms surrounding the metal,” explains Nanda. “Using structure comparison tools, we then looked at these metal micro-environments and clustered them into groups of similar structure.” 

This analysis identified four types of metal sites that were used repeatedly in widely different modern proteins, identifying them as the progenitor ‘Legos’ which may be the closest approximation of primordial protein. These structures have since evolved, over millions of years, to become modern day proteins. So, what did these ancient structures look like?

“A ‘Lego’ represents a local group of amino acids (50-100 residues) that surrounds a single metal.  This includes the amino acids that bind the metal as well as the 2nd-shell neighbors that tune the redox potential of the metal,” explains Nanda. "The study is the first time we've been able to take something with thousands of amino acids and break it down into reasonable chunks that could have had primordial origins." 

A Key to Molecular Engineering?

These ancient structures might also be relevant in the modern world, with the evolutionary process that has built them, over millennia, into modern proteins, holding clues for industrial techniques that seek to replicate proteins.

“The flip side of molecular evolution studies is molecular engineering,” says Nanda.  We can use the rules we obtain from studying how natural proteins build circuits to start to design our own nanoscale components - transistors, diodes, wires - and assemble them into bio-electronic devices.” 

Aside from these immediately practical properties, the findings also represent a window into where humanity came from, when life was at its most basic. Nanda explains: “We think that the modern proteome and databases like the PDB can be used to see back in evolutionary time billions of years to what the earliest proteins looked like.” 

‘Legos’ Yet to be Decoded?

These four structures may represent just the first few progenitors to be unveiled. Nanda hopes future research may dig up 5 or 10 more ‘Legos’. Even then, working out their structure is just the first hurdle. “Now we need to understand how to put these parts together to make more interesting functional molecules," said Nanda. "That's the next grand challenge."

This article was written based on research at Rutgers University.