Using AI, an extreme microbe reveals how the building blocks of life adapt to high pressure

The help of a Google artificial intelligence tool has helped scientists uncover how the proteins of a heat-loving microbe respond to the scorching conditions of the planet’s deepest ocean trenches, offering new insights into how these building blocks of life might have evolved under conditions on early Earth.

The results, published in PRX Lifewill likely spark new studies into the inner workings of proteins and life on other planets, and serve as a successful case study of how artificial intelligence has been able to accelerate this research by decades.

“This work gives us a better idea of ​​how we might design a new protein that can withstand stress and new clues about the types of proteins that might be more likely to exist in high-pressure environments like those on the ocean floor or on another planet,” said Stephen Fried, a chemist at Johns Hopkins University who co-led the research.

Fried’s team subjected Thermus thermophilus, a microorganism widely used in scientific experiments because of its ability to withstand heat, to simulated laboratory pressures that mimic those in the Mariana Trench. Tests revealed that some of its proteins withstand these stress levels because they have built-in flexibility with extra space between their atomic structures, a design that allows them to compress without collapsing.

How a protein’s building blocks, or chains of amino acids, “fold,” or arrange themselves into 3D structures, determines their function. But these structures can be highly sensitive to temperature, pressure, and other environmental factors (as well as biochemical and genetic accidents) that cause them to fold incorrectly and take on dysfunctional shapes.

The analysis shows that 60% of the bacteria’s proteins withstood the pressure while the rest collapsed and their shapes became distorted, particularly at points or sites known to have important biochemical functions. These findings could help explain how other organisms thrive under extreme pressures that would kill most living things.

“Life has obviously evolved to adapt to different environments over billions of years, but evolution can sometimes seem like a magical phenomenon,” Fried said. “Here we really get into the biophysics of how this happens and see that it’s due to a simple geometric solution in the 3D arrangement of the building blocks of these proteins.”

These results demonstrate the potential of artificial intelligence for scientific discovery, Fried said. By incorporating the power of Google’s AlphaFold tool, the team mapped the pressure-sensitive parts of all T. thermophilus proteins. The AI ​​tool predicted the structure of more than 2,500 proteins in the organism, helping the team calculate the correlation between their configurations and their ability to withstand pressure changes — a feat that would have taken decades to achieve with direct measurements alone, Fried said.

Although the model organism is known for its ability to thrive around hot springs or hydrothermal vents rather than its ability to withstand the pressures of the deep ocean, the findings could shed light on deep-ocean life that is vastly understudied — as well as unknown — said author Haley Moran, a Johns Hopkins chemist who studies “extreme” organisms.

“A lot of people predict that if we find alien life, we’ll find it deep in the ocean of a planet or moon. But we don’t fully understand life in our own ocean, where many different species live that not only tolerate what could kill us, but love it and thrive in it,” Moran said. “We take proteins, one of the building blocks of life, and we subject them to these extreme conditions to see how they can adapt to push the limits of life.”

The study results also show that high-pressure tests could reveal additional molecular functions that remain hidden in other organisms. Until now, it was generally thought that pressure levels had to be elevated well above the level of the ocean trench to influence a protein’s biochemistry, said author Richard Gillilan, a Cornell University chemist who helped design the high-pressure experiments.

“We were really taken by surprise, but as we kept checking the numbers and looking at the individual molecular structures, we realized this was a treasure map,” Gillilan said. “We’ve opened a door that will provide many new targets for structural and biophysical studies, perhaps even for drug discovery.”

The team will then conduct experiments on other organisms, particularly those that thrive under high pressure in the deep ocean.

Other authors are Edgar Manriquez-Sandoval and Piyoosh Sharma of Johns Hopkins.