A team led by scientists at Georgia State University simulates the precise transition between the processes of DNA synthesis and proofreading
DNA replication is one of the most important processes in biology, responsible for ensuring that a cell’s genetic material is copied over to new cells efficiently during cell division. But what happens when there is a mistake?
Fortunately, replicative DNA polymerases—the cell’s replication molecular machines—are capable of proofreading the newly synthesized DNA and correcting mistakes made during the DNA replication process. These polymerases detect misincorporated DNA bases and transfer them to a specialized compartment inside of the polymerase to excise them.
If it weren’t for these versatile and efficient machines, the cell’s genetic material would be compromised, potentially leading to abnormal cellular functioning, impaired development, and diseases such as cancer. But just how mistakes are corrected while the polymerase synthesizes a new DNA strand hasn’t been fully understood.
Now, a team at Georgia State University has used the nation’s fastest supercomputer, the IBM AC922 Summit at the US Department of Energy’s (DOE’s) Oak Ridge National Laboratory (ORNL), to find the optimal transition path that a highly accurate bacterial DNA polymerase uses to switch between building and editing DNA. This optimal DNA path serves as a molecular highway, guiding the starting point of the DNA strand as it travels the large distance between the two sites where DNA is synthesized or excised. The work was published in the journal Nature Communications.
“We represented the path between these two—the polymerase and exonuclease states—as a series of replicas of the simulation system that were all optimized and sampled simultaneously,” said Ivaylo Ivanov, researcher at Georgia State University. “Applying path optimization methods to large macromolecular complexes was, until recently, computationally prohibitively expensive. Only with recent advances in GPU technology on massively parallel computing platforms like Summit did it become possible for us to sample the conformational ensemble along the optimal path.”
Image Credit: Ivaylo Ivanov, Georgia State University
Post by Amanda Scott, NA CEO. Follow her on twitter @tantriclens
Thanks to Heinz V. Hoenen. Follow him on twitter: @HeinzVHoenen
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