Researchers Use Comet to Examine a DNA-Editing Enzyme

By Staff report

March 14, 2020

Genome editing stands to change the trajectory of human civilization, with massive implications for treatments of any genetic disease and potential for even broader improvements in human health. The process, however, is currently limited, difficult and expensive, with a number of different organizations exploring a variety of techniques. Now, chemists from the University of California San Diego have applied supercomputing in their quest to make genome editing more viable.

Using molecular dynamics simulations, the researchers focused on an RNA-editing enzyme called “TadA” that evolves into a DNA-editing enzyme. This conversion then makes it useful as precursor for adenine base editors (ABEs): when TadA is paired with a DNA-binding module, the resulting ABE is able to convert adenine (“A”) nucleobases into guanine (“G”) nucleobases. 

“Adenine that is being targeted is within the genome, which is within the nucleus, which, in turn, is within the cell,” explained Kartik Rallapalli, a Ph.D. student at UC San Diego who worked on the research alongside two professors, in an interview with UCSD’s Cynthia Dillon. “Hence, what we are targeting is very tightly guarded. Nature never bothered to have enzymes that could go in there and change things.”

The problem: enzymes like TadA are in short supply. So in an effort to find out what makes TadA tick, the researchers used their simulations to delve into the process that transforms TadA into a DNA-editing enzyme at an extremely granular level. To run those simulations, they turned to Comet, a supercomputer housed by the San Diego Supercomputer Center (SDSC). Comet’s 1944 Intel Haswell-based nodes and 72 Nvidia-based GPU nodes deliver 2.76 peak petaflops.

“The overarching goal of our study is to understand how evolution works in general—how evolutionary changes at the molecular level can train an existing enzyme to do something completely novel,”Rallapalli said. “By gathering atomistic insights into the process, we may be able to learn the rules of the evolutionary game and try to get ahead of natural evolution – try to convert more RNA-editing enzymes into DNA-editing enzymes, which can become novel genome editors.”

Specifically, the researchers examined the relationship between amino acid changes in the enzyme and its DNA-editing abilities. In another study, one of the researchers – Alexis Komor, an assistant professor at UC San Diego – had tested a series of amino acid changes to TadA, building a library of successfully evolved variants. 

“Given the stochastic nature of the evolutionary process that we employed, we had absolutely no idea of how these variants were working,” said Komor. “It’s really hard to study these enzymes inside a cell or even in a test tube. That’s where Kartik came in and provided us with an atomistic understanding of how particular amino acid changes in TadA enable this enzyme to do its chemistry on DNA.”

The researchers are hopeful that this research will help researchers narrow in on the most promising mechanisms for forcing that DNA-editing evolution, pushing genetic editing forward.

“These atomistic insights can focus our actual experimental efforts on certain amino acids, which can significantly reduce the cost and the labor of research and increase our chances of success,” Komor said. “We are thrilled to see what more this combination of simulations and experiments can reveal in the future.”

To read the UC San Diego article about this research, click here.

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