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Molecular Mechanism of Drug Intercalation into DNA

 - Prof. Biman Bagchi, SSCU

   Intercalation into DNA (insertion between a pair of base pairs) is a critical step in the function of many anticancer drugs. Despite its importance, a detailed mechanistic understanding of this process at the molecular level is lacking. We have constructed, using extensive atomistic computer simulations and umbrella sampling techniques, a free energy landscape for the intercalation of the anticancer drug daunomycin into a twelve base pair B-DNA [1]. A similar free energy landscape has been constructed for a probable intermediate DNA minor groove-bound state. These allow a molecular level understanding of aspects of the thermodynamics, DNA structural changes, and kinetic pathways of the intercalation process. Key DNA structural changes involve opening the future intercalation site base pairs toward the minor groove (positive roll), followed by an increase in the rise, accompanied by hydrogen bonding changes of the minor groove waters. The calculated intercalation free energy change is -12.3 kcal/mol, in reasonable agreement with the experimental estimate -9.4 kcal/mol. The results point to a mechanism in which the drug first binds to the minor groove and then intercalates into the DNA in an activated process, which is found to be in general agreement with experimental kinetic results. In a related work, we have studied the water dynamics in the grooves of DNA and observed vastly different dynamical features [2].

References:

  1. A. Mukherjee, R. Lavery, B. Bagchi, and J. T. Hynes, J. Am. Chem. Soc. (ASAP Article)
  2. S. Pal, P. K. Maiti, and B. Bagchi J. Chem. Phys. 25, 234903 (2006).






Figure 1:(a)Atomistic structure of daunomycin. Constructed and equilibrated structures of (b) the intercalated state and (c) the minor groove-bound state. In both figures, DNA is shown in a semitransparent surface representation including ball and stick atom models and residue-based color (yellow for C, green for G, red for A and blue for T), whereas daunomycin is represented via a ball and stick model with element-based CPK color.




Figure 2: Free energy landscape in the umbrella sampling coordinate X and the angle q. The intercalated, minor groove-bound and separated states are indicated, as is the critical region. The green arrowed dashed lines (and their red projections onto the X-q plane) are schematic guides to show the most probable path from separated ® minor groove-bound ® intercalated state through the critical region.