Nucleosome Dynamics at Microsecond Timescale: DNA-Protein Interactions, Water-Mediated Interactions and Nucleosome Formation

Abstract

At the cornerstone of eukaryotic chromatin is the association of DNA with histone proteins to form nucleosomes. Every nucleosome core particle consists of 147 bp of DNA wrapped around and octamer of histones. Many factors (such as DNA sequence, histone variants, post-translational modifications, etc.) can affect the stability and dynamics of nucleosomes, which in turn provide key mechanisms for epigenetic regulation of gene expression. We report an extensive study of nucleosome dynamics and organization via molecular modeling based on all-atom microsecond molecular dynamics simulations. We analyze dynamics of full nucleosomes including linker DNA segments and full-length histones in explicit solvent and compare it to the dynamics of nucleosome core particle and histone octamer alone. Extensively long simulation time scale allows us to address the questions of conformation coupling between histones and DNA as well as study the interaction patterns of flexible histone tails. Detailed analysis of protein-DNA interactions is performed including water-mediated interactions and the role of water molecules in the central nucleosome pore. We analyze the rearrangement of nucleosome structure upon DNA binding and discuss the cooperativity of interactions in nucleosome formation. This work was supported by the Intramural Research Programs of NLM and NCI; and RSF grant No. 14-24-00031 (nucleosome visualization algorithms).