From nucleosomes to chromatin fibers [Elektronische Ressource] : molecular dynamics and Monte-Carlo simulations of nucleosome organization and interactions / presented by Ramona Ettig

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Dissertationsubmitted to theCombined Faculties for the Natural Sciences and for Mathematicsof the Ruperto-Carola University of Heidelberg, Germanyfor the degree ofDoctor of Natural SciencesPresented byDipl. Phys. Ramona Ettigborn in Frankfurt, GermanythOral-examination: October, 13 2010iiFrom nucleosomes to chromatin bers:molecular dynamics and Monte-Carlo simulationsof nucleosome organization and interactionReferees: Prof. Dr. Dr. Christoph CremerPD Dr. Karsten RippeivFrom nucleosomes to chromatin bers: molecular dynamics and Monte Carlosimulations of nucleosome organization and interactionChromosomes consist of a chain of nucleosomes, in which DNA wraps almost twice arounda histone protein core. Nucleosomes are stable complexes and their position along the DNAregulates DNA accessibility. The underlying mechanisms of this process are still not un-derstood well. In this thesis, molecular dynamics, steered molecular dynamics and MonteCarlo simulations were conducted to elucidate nucleosome organization and the folding ofnucleosome chains into chromatin bers at di erent length scales. The all-atom resolutionof molecular dynamics simulations revealed a novel map of histone-DNA interaction sitesextending experimental ndings. By applying external forces the complete DNA unwrappingfrom the protein core at atomic resolution was investigated.

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Dissertation
submitted to the
Combined Faculties for the Natural Sciences and for Mathematics
of the Ruperto-Carola University of Heidelberg, Germany
for the degree of
Doctor of Natural Sciences
Presented by
Dipl. Phys. Ramona Ettig
born in Frankfurt, Germany
thOral-examination: October, 13 2010iiFrom nucleosomes to chromatin bers:
molecular dynamics and Monte-Carlo simulations
of nucleosome organization and interaction
Referees: Prof. Dr. Dr. Christoph Cremer
PD Dr. Karsten RippeivFrom nucleosomes to chromatin bers: molecular dynamics and Monte Carlo
simulations of nucleosome organization and interaction
Chromosomes consist of a chain of nucleosomes, in which DNA wraps almost twice around
a histone protein core. Nucleosomes are stable complexes and their position along the DNA
regulates DNA accessibility. The underlying mechanisms of this process are still not un-
derstood well. In this thesis, molecular dynamics, steered molecular dynamics and Monte
Carlo simulations were conducted to elucidate nucleosome organization and the folding of
nucleosome chains into chromatin bers at di erent length scales. The all-atom resolution
of molecular dynamics simulations revealed a novel map of histone-DNA interaction sites
extending experimental ndings. By applying external forces the complete DNA unwrapping
from the protein core at atomic resolution was investigated. This revealed intermediates of
the pathway and an important contribution of the unstructured histone tails to nucleosome
stability. Simulations of stretching coarse-grained chromatin bers showed that experimen-
tal force-extension curves alone are insu cient to identify ber geometry parameters and
internucleosomal interaction strength. The chromatin ber model was extended by a new
description for DNA electrostatics to enable the translocation of nucleosomes within the ber.
The e ect of this process on the stability of the ber was strongly dependent on its geometry.
Vom Nukleosom zur Chromatin Faser: Molekulardynamik und Monte-Carlo Sim-
ulationen zur Organisation und Interaktion von Nukleosomen
Chromosomen bestehen aus einer Kette von Nukleosomen, in denen sich DNA fast zweimal
um einen Histonproteinkern wickelt. Nukleosome sind stabile Komplexe und ihre Position
entlang der DNA reguliert die DNA Zug anglichkeit. Die zugrunde liegenden Prozesse sind
bislang noch nicht vollst andig verstanden. In dieser Doktorarbeit wurden Molekulardy-
namik, gerichtete Molekulardynamik sowie Monte-Carlo Simulationen durchgefuhrt, um Nuk-
leosomenorganisation und die Faltung von Nukleosomenketten in Chromatinfasern auf ver-
schiedenen L angenskalen aufzukl aren. Mit Hilfe der atomaren Au osung in Molekularen Dy-
namik Simulationen konnten eine neue Interaktionskarte zwischen DNA und Histonproteinen
erstellt werden, die bisherige experimentelle Ergebnisse erweitert. Das vollst andige Abwick-
eln der DNA vom Proteinkern mit atomarer Au osung wurde durch Anlegen externer Kr afte
untersucht. Dabei wurden Zwischenzust ande im Reaktionsweg und ein wichtiger Ein uss der
unstrukturierten Histonarme auf die Stabilit at des Nukleosoms entdeckt. Ziehsimulationen
von gr ober modellierten Chromatinfasern zeigten, dass experimentelle Kraft-Abstandskurven
alleine nicht ausreichen, die Fasergeometrie und internukleosomale Wechselwirkungsst arken
zu bestimmen. Das Chromatinfasermodell wurde um eine neue Beschreibung der Elektro-
statik der DNA erweitert. Hiermit war es m oglich, Nukleosomen innerhalb einer Chromat-
infaser zu verschieben. Erste Simulationen zeigten einen starken Ein uss der Fasergeometrie
auf die Faserstabilit at.vito my parents ...viii