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Giving Structure to the Genome. Thomas (Tom) C. Bishop Louisiana Tech University 2013 Associate Professor of Chemistry & Physics. Nucleosome Positioning and Many Nucleosome Simulations.
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Giving Structure to the Genome Thomas (Tom) C. Bishop Louisiana Tech University 2013 Associate Professor of Chemistry & Physics
Nucleosome Positioning andMany Nucleosome Simulations The yeast genome contains 16 chromosomes. Here we show the most stable nucleosomes, found on each chromosome. We simulate a 21bp window about each experimentally determined position. The movie represents only the 336 starting positions for our HT-HP study. Solvent is not shown. (16chroms * 21positions = 336) Approx 160K atoms/simulation. Total run time to complete the study ~ 8,000,000 SU http://dna.engr.latech.edu/~bishop/Movies/16-yeast-positions.mpg
601: the Control Simulation The sequence known as 601 is an artificially strong nucleosome positioning sequence. Here we show the “kinks” as observed during a 50ns all atom MD simulation. Kinks form and heal on the nanosecond time frame. A kink is defined here as having all six DNA helical parameters greater than 1s away from values appropriate for DNA free in solution. http://dna.engr.latech.edu/~bishop/Movies/601-trajectory.mpg
Kink behavior vs. sequence position in Chromosome XV of S. cerevisiae On the next slide instead of looking at the dynamics of individual nucleosomeswe display only the frequency at which kinking occurs during individual 20ns mononucleosome simulations. The 21 nucleosomes are arranged in “reading” order . The second nucleosome represents a sequence shift of 1bp relative to the first. The third nucleosome is a shift of 2bp, etc... etc… The nucleosome in the center of the page is the one identified by experiment to be the most stable, but it has more kinks than the nucleosome that is middle + 2. We propose that kinks are indicative of a stress release mechanism for sequences that do not favor nucleosome formation. Sequences that can form the superhelix without kinking should be more stable than kinked sequences, i.e. the stress is less. The nucleosome at the middle +2 should be stable.
Kink frequency for 21 nucleosome window of Chromosome XV http://dna.engr.latech.edu/~bishop/Movies/chr15-kink-hp6-std1-frequency-rotate.mpg
From positioning to folding. If we know the nucleosome positions, then we can fold nucleosome arrays into chromatin. Our Interactive Chromatin Modeling (I C M) web server allows users to do this in near real time for segmentsof DNA containing up to 20,000 basepairs. You can roll you own chromatin at : http://dna.engr.latech.edu.edu/icm
Future Plans • Optimize the nucleosome simulation work flow to allow “on-demand” simulation and analysis of individual nucleosomesas a benchtop tool for experimentalists. We have demonstrated that given 24,000 CPUs the threading simulations including analysis is a one day computation. • Combine all atom modeling with interactive chromatin modeling to investigate role of nucleosome-nucleosome interactions in chromatin folding. Our ICM toolset http://dna.engr.latech/edu -> Chromatin Folding already generates the necessary inputs for such studies. • Combine the coarse-grained modeling in ICM with bioinformatics tools to add a structural component to bioinformatics, e.g. color folded chromosomes by function to generate a computational FISH.
