The Role of Electrostatics in Sequence Dependent Nucleosome Stability Analysis

Abstract

Nucleosome stability is strongly sequence dependent; yet the conformation of the DNA in the nucleosome is sequence independent. The nucleosome conformation is determined only by the histone octamer, and there is an energy penalty for deforming free DNA into this conformation. By comparing all atom molecular models and coarse grained elastic rod based models to experimentally determined free energies, we demonstrate that the contributions to the free energy of nucleosome formation arise from two sources: electrostatics and the local material properties of DNA.The primary contribution to electrostatic energy in the nucleosome comes from the highly charged yet conserved phosphate backbone of DNA. Since all DNA sequences assume the same conformation in the nucleosome the electrostatic energy associated with the nucleosome conformation of DNA is largely sequence invariant. Thus the electrostatic energy contribution to nucleosome stability is defined not by the conformation of DNA in the nucleosome but by the conformation of free DNA. The free conformation rather than the bound conformation determines the binding free energy.The material properties of DNA (elastic and van der Waals energies) behave quite differently. These energies are strongly dependent upon the sequence and conformation of the DNA. The conformation of free DNA tends to minimize these energies. When DNA binds the histone octamer and assumes the nucleosomal DNA conformation, the elastic and van der Waals energies associated with such deformation are also strongly sequence dependent. If the DNA sequence possesses intrinsic conformational properties that match those of the nucleosome or if the sequence is suitably flexible then the energy penalty is lower than for sequences which do not possess such characteristics. Both the free and bound states contribute to binding free energy.