Visualizing the Fundamental Process of DNA Strand Separation

For the first time, scientists have captured the exact moment DNA begins to unravel, shedding light on a fundamental chemical process that enables DNA to serve as the blueprint for life. A recent study from King Abdullah University of Science and Technology (KAUST), published in Nature, details how this unraveling sets the stage for all subsequent steps in DNA replication.

This direct observation clarifies the essential processes that allow cells to replicate their genetic material with remarkable reliability—an absolute necessity for growth and reproduction.

The research, led by KAUST Assistant Professor Alfredo De Biasio and Professor Samir Hamdan, provides the most detailed account yet of the early stages of DNA replication. Using cryo-electron microscopy and deep learning, the team captured how the helicase enzyme Simian Virus 40 Large Tumor Antigen interacts with DNA across 15 atomic states. These observations illustrate how the helicase compels DNA to unravel, offering unprecedented insights not only into helicase function but also into the dynamic behavior of enzymes at the atomic level.

While scientists have long understood the importance of helicases in DNA replication, the precise coordination between DNA, helicases, and ATP remained unclear. “They did not know how DNA, helicases, and ATP work together in a coordinated cycle to drive DNA unwinding,” explained De Biasio.

The discovery builds upon the landmark 1953 breakthrough when Watson and Crick revealed DNA’s double-helix structure. For replication to occur, the helix must first unwind, splitting into two single strands.

Helicases function like molecular engines, fueled by adenosine triphosphate (ATP)—the same molecule that powers muscle contractions. Similar to how the pistons in an engine are driven by burning fuel, the six subunits of a helicase enzyme use ATP to progressively unwind DNA.

The study found that as ATP is consumed, it reduces the helicase's physical constraints, allowing it to move along the DNA and continue unwinding the double strand. Rather than prying DNA apart in a single motion, the helicase undergoes a series of conformational changes, gradually destabilizing and separating the strands. ATP hydrolysis acts like a spring-loaded mechanism, propelling the helicase forward and pulling the DNA strands apart.

A key discovery by the KAUST researchers is that two helicases work in tandem, melting DNA at two separate locations to initiate the unwinding process. Due to DNA’s chemical structure, helicases can only move in one direction along a single strand. By binding at two points simultaneously, they enable unwinding in both directions, achieving a level of energy efficiency unique to natural molecular machines.

According to De Biasio, this efficiency has implications beyond fundamental biology. “From a design perspective, helicases exemplify energy-efficient mechanical systems. Engineered nanomachines using entropy switches could harness similar energy-efficient mechanisms to perform complex, force-driven tasks.”

This breakthrough not only deepens our understanding of DNA replication but also provides a potential blueprint for developing advanced nanotechnology inspired by nature’s most efficient molecular machines.