KAUST Scientists Observe DNA Initial Unwinding at Atomic Level

A new study from King Abdullah University of Science and Technology (KAUST), published in Nature, has captured the moment DNA begins to unwind, allowing for all the events that follow in DNA replication. This direct observation sheds light on the fundamental mechanisms enabling cells to duplicate their genetic material, essential for growth and reproduction.
 According to a recent KAUST press release, the research team, led by KAUST Assistant Professor Alfredo De Biasio and Professor Samir Hamdan, used cryo-electron microscopy (cryo-EM) and deep learning techniques to observe the interaction of the helicase enzyme Simian Virus 40 Large Tumor Antigen with DNA. Their research provided the most detailed description of the very first steps of DNA replication, detailing 15 atomic states that illustrate how the helicase forces DNA to unwind.
 "The achievement is not only a milestone in helicase research, but also a milestone in observing the dynamics of any enzyme at atomic resolution," the release stated.
 Upon binding, helicases melt the DNA, breaking the chemical bonds holding the double helix together. They then pull the two strands apart, allowing other enzymes to complete the replication. Without this first step, no DNA can be replicated. In this way, helicases are machines or, because of their size, nanomachines.
 The study found that as adenosine triphosphate (ATP) is consumed, it reduces physical constraints that allow the helicase to proceed along the DNA, unwinding more and more of the double strand. Thus, ATP consumption acts as a switch that increases the amount of entropy – or disorder – in the system, freeing the helicase to move along the DNA.
 De Biasio said, "The helicase uses ATP not to pry DNA apart in one motion, but to cycle through conformational changes that progressively destabilize and separate the strands."
 The release also highlighted that among the many discoveries made by the KAUST scientists was that two helicases melt the DNA at two sites at the same time to initiate the unwinding. The chemistry of DNA is such that nanomachines move along a single DNA strand in one direction only. By binding at two sites simultaneously, the helicases coordinate so that the winding can happen in both directions with an energy efficiency unique to natural nanomachines.
 That efficiency, emphasized De Biasio, makes the study of DNA replication more than an attempt to answer the most fundamental scientific questions about life; it also makes helicases models for the design of new nanotechnology.
 "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," he said.