Understanding Cu⁺² binding with DNA: A molecular dynamics study comparing Cu²⁺ and Mg²⁺ binding to the Dickerson DNA

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Copper ions (Cu²⁺) cause DNA damage through reactive oxygen species (ROS).
• Similar ionic radii suggest Cu²⁺ and Mg²⁺ may bind DNA similarly, but atomic-level binding details are unclear.
• Understanding Cu²⁺ binding sites (phosphate, grooves) in double-stranded DNA (dsDNA) is crucial.

Purpose of the Study:

• To investigate Cu²⁺ ion binding to a B-type dodecamer dsDNA (Dickerson DNA) at the atomic level using molecular dynamics (MD) simulations.
• To compare the binding characteristics of Cu²⁺ and Mg²⁺ ions with dsDNA.
• To elucidate the mechanisms of Cu²⁺-DNA interactions and their role in ROS-mediated DNA damage.

Main Methods:

• Molecular dynamics (MD) simulations were performed on the Dickerson DNA dodecamer.
• The binding of Cu²⁺ and Mg²⁺ ions to dsDNA was analyzed.
• Binding sites and interactions, including hydration shell dynamics, were investigated.

Main Results:

• The first hydration shell of Cu²⁺ is labile, enabling both direct and indirect dsDNA binding (via water displacement or through the hydration shell).
• Cu²⁺ ions exhibit stronger binding propensity to dsDNA compared to Mg²⁺ ions.
• Both ions show a similar binding order preference: phosphates > major groove > minor groove.

Conclusions:

• Cu²⁺ exhibits unique binding behavior with dsDNA due to its labile hydration shell, differing from Mg²⁺.
• The findings provide atomic-level insights into Cu²⁺-DNA interactions.
• This research aids in understanding and rationalizing Cu²⁺-induced ROS-mediated DNA damage.