Molecular Dynamics Simulation Workflow for Nucleosome Studies

Abstract

Nucleosomes are the building blocks of eukaryote genomes. Given that a nucleosome contains 147 base pairs of DNA, the DNA sequence complexity is ∼ 4147. With the advent of genome wide association studies attention can be focused on one nucleosome. Today's supercomputers and simulation tools are sufficiently powerful to conduct comparative studies of ensembles representing 10's to 100's of mononucleosomes in a few days. Here we demonstrate a workflow that characterizes 21 different positions of 601: 10 upstream, 10 downstream and the ideal position in atomic detail. Atomic models were constructed by automatically docking the 601-177 fragment to the histone core of 1KX5. In all 21 simulations, the superhelix geometry evolves in less than 100 ns to a conformation that is significantly different from the original 1KX5 geometry. We previously demonstrated that all x-ray structures of the nucleosome exhibit a specific distribution of Roll, Slide, and Twist. Twelve Fourier components are necessary and sufficient to describe the DNA base pair step parameters required to recreate a nucleosome superhelix in atomic resolution. Here we employ our Fourier filtering technique to show that 100 ns is sufficient to observe global conformational changes associated with positioning and mispositioning the 601-177 fragment. Specifically, ideal positioning yields a DNA superhelix conformation with a significantly different distribution of Slide than mispositioned nucleosomes. The phase and amplitude of Slide associated with wave number 14, approximately the DNA helix repeat 146bp/14, is strongly influenced by nucleosome mispositioning. Thus we have validated a workflow that allows us to efficiently simulate and analyze nucleosomes and demonstrated that simulations as short as 100 ns are sufficient to investigate sequence specific properties of the nucleosome. All simulation and analysis data is published via our iBIOMES server at http://www.latech.edu/∼bishop.