Conformational selection and dynamic adaptation upon linker histone binding to the nucleosome.
Linker histones are essential for DNA compaction in chromatin. They bind to nucleosomes in a 1:1 ratio forming chromatosomes. Alternative configurations have been proposed in which the globular domain of the linker histone H5 (gH5) is positioned either on- or off-dyad between the nucleosomal and linker DNAs. However, the dynamic pathways of chromatosome assembly remain elusive. Here, we studied the conformational plasticity of gH5 in unbound and off-dyad nucleosome-bound forms with classical and accelerated molecular dynamics simulations. We find that the unbound gH5 converts between open and closed conformations, preferring the closed form. However, the open gH5 contributes to a more rigid chromatosome and restricts the motion of the nearby linker DNA through hydrophobic interactions with thymidines. Moreover, the closed gH5 opens and reorients in accelerated simulations of the chromatosome. Brownian dynamics simulations of chromatosome assembly, accounting for a range of amplitudes of nucleosome opening and different nucleosome DNA sequences, support the existence of both on- and off-dyad binding modes of gH5 and reveal alternative, sequence and conformation-dependent chromatosome configurations. Taken together, these findings suggest that the conformational dynamics of linker histones and nucleosomes facilitate alternative chromatosome configurations through an interplay between induced fit and conformational selection.
Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg 69118, Germany The Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS), Heidelberg University, Heidelberg 69120, Germany.
Mehmet Ali
MA
Öztürk
Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg 69118, Germany.
Georgi V
GV
Pachov
Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg 69118, Germany Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg 69120, Germany Interdisciplinary Center for Scientific Computing (IWR), Heidelberg 69120, Germany rebecca.wade@h-its.org.
Rebecca C
RC
Wade
Computational Structural Biology Laboratory, Department of Cellular and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster 48149, Germany Center for Multiscale Theory and Computation, Westfälische Wilhelms University, Münster 48149, Germany vlad.cojocaru@mpi-muenster.mpg.de.
Vlad
V
Cojocaru
D004247:DNA / Q000737:chemistry; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D009707:Nucleosomes / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D013936:Thymidine / Q000378:metabolism
D006657:Histones; D009707:Nucleosomes; D004247:DNA; D013936:Thymidine