Based on experimental data, computer-based molecular dynamics simulations and complex electronic structure calculations, the paper is the first to describe how sodium ions could control the migration of electron holes – also known as radical cations – through DNA. The electron holes, positively charged locations in the DNA structure, are created by normal cellular oxidation processes and everyday events such as exposure to sunlight. Migrating through the DNA to distances up to 30 nanometers away from their site of origin, the electron holes ultimately reach certain sites where they may initiate reactions that can damage the genetic coding.
"Our paper presents a new way of thinking about what controls electrical charge transport in DNA," said Gary Schuster, a professor in the School of Chemistry and Biochemistry at the Georgia Institute of Technology and dean of its College of Sciences. "It is the motions of the water molecules, the sodium ions, the backbone of the DNA and the bases of the DNA that altogether control the movement of charge in the DNA. It's clear that we must consider both the DNA and its environment."
Underlying the charge migration mechanism unveiled in this study are two physical principles: (1) like electrical charges electrostatically repel one another, and (2) thermal energy induces random motion – known as stochastic dynamic fluctuations -- among the microscopic constituents of matter: ions, atoms and molecules.
In a 1999 paper published in Proceedings of the National Academy of Sciences, Schuster and his colleagues suggested that electrical charge moves through DNA in a "Slinky-like" process in which the molecule distorts itself in an effort to locally stabilize the charge. The new work seeks to explain why the charge moves at all, and to elucidate the dynamical mechanism of long-range transport in DNA.
In a nutshell, the paper's authors argue that the positively charged electron holes – created by the removal of an electron -- move when approached by positively charged sodium ions hydrated in the aqueous medium surrounding the DNA. Circulated by thermal energy in a random way, the diffusing sodium ions are attracted to specific locations in the DNA, such as the negatively charged phosphates that are part of the DNA backbone and certain atoms of the nucleo-bases.
"The electron holes in the DNA simply don't like to be near the positively charged sodium ions, so the stochastic motion of the solvated ions initiates and gates the motion of the electron holes," explained Uzi Landman, Regents' professor of physics and director of the Georgia Tech Center for Computational Materials Science. "The motion of one charge repels the other, resulting in a correlated dance of the two."
Using one of the largest electronic structure calculations ever done, Landman and colleagues Robert Barnett and Charles Cleveland predicted how the process would work theoretically. These computations were performed mainly on an IBM SP2 parallel computer at the Georgia Tech Center for Computational Materials Science, and on other supercomputers at national centers.
To provide experimental corroboration, Schuster and collaborator Abraham Joy modified a portion of DNA backbone by replacing the negatively charged phosphates with a methylphosphonates of the same size – but not carrying a formal electrical charge. They found that the modified backbone, no longer able to attract sodium ions, became an obstacle to the migration of electrical charge.
"In doing so we were motivated by intuitive arguments, supported by our molecular dynamics simulations, that the affinity for sodium ions to be around the DNA is greatly diminished by reducing the negative charge on the phosphates," explained Landman. "Since the sodium ions show a reduced propensity to reside near the modified region of the DNA molecule, there is nothing there to effectively modulate and gate the motion of the positively charged electron holes. That reduces the probability of charges moving across the modified region."
Beyond the implications for DNA damage in living organisms, the work also has implications for proposed uses of DNA in nanotechnology. There, the self-recognition and self-assembly capabilities of the molecule make it potentially useful for sensors, tiny conductive structures and other applications.
But the work of Landman and Schuster suggests that the electronic transport properties may not be favorable outside of DNA's native environment.
"Even when it conducts, DNA is not a good conductor in the sense of the speed at which charge flows through it," said Landman. "Under the best of circumstances, it is a slow conductor. Under most other circumstances, especially in dry form, it is simply an insulator."
Beyond the conclusions, Schuster believes the work demonstrates the value of close collaboration between experimental and theoretical scientists.
"For the past few years, we have been looking at charge transport in DNA from an experimental point of view, gathering data and making certain observations," he said. "With Uzi Landman's contribution, we were able to bring these observations together in a new and coherent way that allowed us to formulate a theory for charge transport in DNA that encompasses not only the data we have been able to gather, but also information gathered by other laboratories around the world."
The ability to quickly test experimental results against theory and to refine theory based on new experiments offers a powerful tool. "We have achieved the ability to communicate between experiment and theory in real time," Landman said. "Theory and experiment have formed a new partnership," added Schuster.
For the future, Landman and Schuster hope to study the individual steps involved in charge migration and the complex reactions that cause damage to DNA. They also want to determine whether DNA strands contain "dumps," non-coding sections designed to capture electrical charge and protect more critical components of genomic DNA.
The work was sponsored by the National Science Foundation the U.S. Department of Energy, and the Air Force Office of Scientific Research.
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Technical Contacts: Gary Schuster (404-894-3300); E-mail: (gary.schuster@cos.gatech.edu) or Uzi Landman (404-894-3368); E-mail: (uzi.landman@physics.gatech.edu).
Visuals Available: Molecular dynamics simulation graphicss showing charge moving through the DNA, portraits of research team posed with DNA model, portraits of Landman and Schuster posed with DNA model and computer graphic.
Writer: John Toon
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Science