Comp Chem Research Developments

April 13th, 2005

The contribution of phosphate-phosphate repulsions to the free energy of DNA bending

The packaging of nucleic acids, especially DNA, is of vital importance to all life-forms from viruses to multicellular organisms.  Human cells, for example, contain approximately 2 meters of DNA packed into a nucleus with a radius of 3 µm.  This represents a million-fold reduction in the effective packing volume of DNA in the nucleus relative to that in solution.  In addition to its role in the packaging of genetic material, DNA bending is also important for the regulation of gene expression and protein-DNA binding.  It is of fundamental importance therefore to understand the nature of the forces that govern the bending of charged DNA molecules into non-linear structures and quantify the magnitudes of their associated energetic factors.


Recently, the research group of Prof. Darrin York of the Department of Chemistry along with graduate students Kevin Range and Evelyn Mayaan, and in collaboration with Prof. L. James Maher, III of the Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, have studied the energetics of DNA bending with theoretical models.


Figure 1.  The structure of a 71 base pair bent DNA model illustrating average counter-ion occupations at the phosphates calculated by Monte Carlo simulation using a linear-scaling Green's function solvation approach.Red indicates higher occupancy.  The bent DNA model was based on the crystallographic structure of approximately one full turn of histone-bound DNA in a nucleosome core particle (PDB entry 1AOI).  The calculations predict that phosphate-phosphate repulsions account for approximately 30 percent of the total free energy required to bend DNA from canonical linear B-form into the conformation found in the nucleosome core particle.

In this work, a linear-scaling Green's function solvation method was employed, along with Monte Carlo simulation of counterion occupations at the phosphate residues, in order to quantify the preferential ion and solvation stabilization of bent versus linear DNA.  From these calculations, they were able to predict that the electrostatic phosphate-phosphate contribution to DNA bending is on the order of 30 percent - a substantial, but not fully dominating effect.    This work is featured on the cover of a recent issue of Nucleic Acids Research 33(4) 1257 (2005). A movie showing how the counterion distribution changes with ion load is also available.