The labelling of proteins and nucleic acids with fluorescent probes is a powerful approach to map out the site-specific structure of such systems. The Marcus group has performed spectroscopic studies on duplex DNA constructs containing cyanine (Cy3) chromophore(s). The monomer unit is incorporated into the sugar-phosphate backbone and the dimer units are at opposite positions within complementary single-strands. These experiments are sensitive to the exciton coupling within the Cy3 dimer, and thereby provide information about the local conformation and dynamics of the sugar-phosphate backbones at the labeling positions. The separation between Cy3 monomers and their relative orientation are among the main structural parameters that affect these measurements. In order to gain further insights into the local conformations of the Cy3 dimer, we computationally simulate this system using classical molecular dynamics (MD), and estimate the exciton coupling between the chromophores using single reference quantum mechanical methods. The MD simulations show that the dimer conformation is largely affected by the intra-dimer (Cy3-Cy3) stacking and vicinal Cy3-DNA base stacking. To understand the effect of the environment on the coupling, we ran ab initio calculations in gas phase, implicit solvent, and including the actual DNA environment using QM/MM calculations. Accurate transition atomic charges (tq) are obtained and used to calculate the exciton couplings for the various conformations. The tq model improves the proximity limitations of the point dipole approximation and provides accurate couplings.  We present the couplings resulting from a variety of equilibrated simulation structures. We also show the simulated absorption and CD spectra obtained from QM/MM calculations.

Simulation of duplex DNA containing internally labeled Cy3 dimers

ACS Fall 2021

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